WO2017005668A1 - ARYL SULTAM DERIVATIVES AS RORc MODULATORS - Google Patents

ARYL SULTAM DERIVATIVES AS RORc MODULATORS Download PDF

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Publication number
WO2017005668A1
WO2017005668A1 PCT/EP2016/065643 EP2016065643W WO2017005668A1 WO 2017005668 A1 WO2017005668 A1 WO 2017005668A1 EP 2016065643 W EP2016065643 W EP 2016065643W WO 2017005668 A1 WO2017005668 A1 WO 2017005668A1
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Prior art keywords
methyl
phenyl
dioxo
difluoro
thiazinan
Prior art date
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PCT/EP2016/065643
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French (fr)
Inventor
Olivier RENE
Benjamin Fauber
David Vesey
Paul WINSHIP
Tammy LADDUWAHETTY
Original Assignee
F. Hoffmann-La Roche Ag
Genentech, Inc.
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Application filed by F. Hoffmann-La Roche Ag, Genentech, Inc. filed Critical F. Hoffmann-La Roche Ag
Publication of WO2017005668A1 publication Critical patent/WO2017005668A1/en
Priority to US15/847,400 priority Critical patent/US20180263996A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the invention pertains to compounds that modulate the function of retinoid-receptor related orphan receptor RORc (RQRy) and use of such compounds for treatment of autoimmune diseases
  • T helper 17 cells are interleukin (IL)-17 secreting CD4+ T cells involved in pathogenesis of autoimmune diseases such as rheumatoid arthritis, irritable bowel disease, psoriasis, psoriatic arthritis and spondyloarthridities.
  • the retinoic acid-related orphan receptor ⁇ (RORy or RORc) is recognized as a transcription factor necessary for Thl7 cell differentiation.
  • RORc is an orphan member of the nuclear hormone receptor subfamily that includes RORa (RORa) and RORp (RORb). RORc controls gene transcription by binding to DNA as a monomer. Selective modulation of RORc has been proposed as a route to discovery and development of Thl7 cell-associated autoimmune diseases.
  • the invention p
  • A is a group selected from:
  • p is from 0 to 3;
  • s is from 0 to 3 ;
  • R is: hydrogen; or Ci- 6 alkyl which may be unsubstituted or substituted one or more times with halo;
  • each R e is independently: hydrogen; Ci- 6 alkyl; halo; Ci- 6 alkoxy; or cyano; wherein the Ci_ 6 alkyl moieties may be unsubstituted or substituted one or more times with halo.
  • the compound may be selected from:
  • the invention also provides and pharmaceutical compositions comprising the compounds, methods of using the compounds, and methods of preparing the compounds.
  • Alkyl means the monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms.
  • “Lower alkyl” refers to an alkyl group of one to six carbon atoms, i.e. Ci-C 6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec -butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
  • Alkenyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g. , ethenyl, propenyl, and the like.
  • Alkynyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g. , ethynyl, propynyl, and the like.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.
  • alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
  • Alkoxyalkyl means a moiety of the formula R a -0-R b -, where R a is alkyl and R b is alkylene as defined herein.
  • exemplary alkoxyalkyl groups include, by way of example, 2-methoxy ethyl, 3-methoxypropyl, 1 -methyl -2 -methoxyethyl, l-(2-methoxyethyl)-3-methoxypropyl, and l-(2- methoxyethyl)-3 -methoxypropyl.
  • Alkoxyalkoxy means a group of the formula -O-R-R' wherein R is alkylene and R' is alkoxy as defined herein.
  • Alkylcarbonyl means a moiety of the formula -C(0)-R, wherein R is alkyl as defined herein.
  • Alkoxycarbonyl means a group of the formula -C(0)-R wherein R is alkoxy as defined herein.
  • Alkylcarbonylamino means a group of the formula -R-C(0)-NR'- wherein R is alkyl and R' is hydrogen or alkyl.
  • Alkylcarbonylalkyl means a group of the formula -R-C(0)-R' wherein R is alkylene and R' is alkyl as defined herein.
  • Alkoxyalkylcarbonyl means a moiety of the formula -C(0)-R-R' , wherein R is alkylene and R' is alkoxy as defined herein.
  • Alkoxycarbonylalkyl means a group of the formula -R-C(0)-R wherein R is alkylene and R' is alkoxy as defined herein.
  • Alkoxycarbonylamino means a moiety of the formula R-C(0)-NR'-, wherein R is alkoxy and R' is hydrogen or alkyl as defined herein.
  • Alkoxycarbonylaminoalkyl means a moiety of the formula R-C(0)-NR'-R"-, wherein R is alkoxy, R' is hydrogen or alkyl, and R" is alkylene as defined herein.
  • Alkoxycarbonylalkoxy means a group of the formula -0-R-C(0)-R' wherein R is alkylene and R' is alkoxy as defined herein.
  • Haldroxycarbonylalkoxy means a group of the formula -0-R-C(0)-OH wherein R is alkylene as defined herein.
  • Alkylaminocarbonylalkoxy means a group of the formula -0-R-C(0)-NHR' wherein R is alkylene and R' is alkyl as defined herein.
  • Dialkylaminocarbonylalkoxy means a group of the formula -0-R-C(0)-NR'R" wherein R is alkylene and R' and R" are alkyl as defined herein.
  • Alkylaminoalkoxy means a group of the formula -O-R-NHR' wherein R is alkylene and R' is alkyl as defined herein.
  • Dialkylaminoalkoxy means a group of the formula -O-R-NR'R' wherein R is alkylene and R' and R" are alkyl as defined herein.
  • Alkylsulfonyl means a moiety of the formula - S0 2 -R, wherein R is alkyl as defined herein.
  • Alkylsulfonylalkyl means a moiety of the formula -R'-S0 2 -R" where where R' is alkylene and R" is alkyl as defined herein.
  • Alkylsulfonylalkoxy means a group of the formula -0-R-S0 2 -R' wherein R is alkylene and R' is alkyl as defined herein.
  • Amino means a moiety of the formula -NRR' wherein R and R' each independently is hyrdogen or alkyl as defined herein. "Amino thus includes “alkylamino (where one of R and R' is alkyl and the other is hydrogen) and “dialkylamino (where R and R' are both alkyl.
  • Aminocarbonyl means a group of the formula -C(0)-R wherein R is amino as defined herein.
  • N-hydroxy-aminocarbonyl means a group of the formula -C(0)-NR-OH wherein R is hydrogen or alkyl as defined herein.
  • N-alkoxy-aminocarbonyl means a group of the formula -C(0)-NR-R' wherein R is hydrogen or alkyl and R' is alkoxy as defined herein.
  • Aminocarbonylaminoalkyl means a group of the formula R 2 N-C(0)-NR'-R"- wherein each R is independently hydrogen or alkyl, R' is hydrogen or alkyl, and R" is alkylene as defined herein.
  • N-alkyl-aminocarbonyl means a group of the formula -C(0)-NH-R wherein R is alkyl as defined herein.
  • N-hydroxy-N-alkylaminocarbonyl means a group of the formula -C(0)-NRR' wherein R is alkyl as defined herein and R' is hydroxy.
  • N-alkoxy-N-alkylaminocarbonyl means a group of the formula -C(0)-NRR' wherein R is alkyl and R' is alkoxy as defined herein.
  • N ⁇ -di-C ! ⁇ alkyl-aminocarbonyl means a group of the formula -C(0)-NRR' wherein R and R' are alkyl as defined herein.
  • Aminosulfonyl means a group of the formula -S0 2 -NH 2 .
  • N-alkylaminosulfonyl means a group of the formula -S0 2 -NHR wherein R is alkyl as defined herein.
  • ⁇ , ⁇ -dialkylaminosulfonyl means a group of the formula -S0 2 -NRR' wherein R and R' are alkyl as defined herein.
  • Alkylsulfonylamino means a group of the formula -NR'-S0 2 -R wherein R id alkyl and R' is hydrogen or alkyl as defined herein.
  • N-(alkylsulfonyl)-aminoalkyl means a group of the formula -R-NH-S0 2 -R' wherein R is alkylene and R' is alkyl as defined herein.
  • N-(Alkylsulfonyl)aminocarbonyl means a group of the formula -C(0)-NH-S0 2 -R wherein wherein R is alkyl as defined herein.
  • N-(Alkylsulfonyl)-N-alkylaminocarbonyl means a group of the formula -C(0)-NR-S0 2 -R' wherein wherein R and R' are alkyl as defined herein.
  • N-Alkoxyalkyl-aminocarbonyl means a group of the formula -C(0)-NR-R'-OR” wherein R is hydrogen or alkyl, R' is alkylene, and R" is alkyl as defined herein.
  • N-Hydroxyalkyl-aminocarbonyl means a group of the formula -C(0)-NR-R'-OH" wherein R is hydrogen or alkyl and R' is alkylene as defined herein.
  • Alkoxyamino means a moiety of the formula -NR-OR' wherein R is hydrogen or alkyl and R' is alkyl as defined herein.
  • Alkylsulfanyl means a moiety of the formula -SR wherein R is alkyl as defined herein.
  • Aminoalkyl means a group -R-R' wherein R' is amino and R is alkylene as defined herein.
  • aminoalkyl includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like.
  • the amino moiety of “aminoalkyl” may be substituted once or twice with alkyl to provide
  • alkylaminoalkyl and “dialkylaminoalkyl” respectively.
  • alkylaminoalkyl includes
  • methylaminomethyl methylaminoethyl, methylaminopropyl, ethylaminoethyl and the like.
  • Dialkylaminoalkyl includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N- methyl-N-ethylaminoethyl, and the like.
  • Aminoalkoxy means a group -OR-R' wherein R' is amino and R is alkylene as defined herein.
  • Alkylsulfonylamido means a moiety of the formula -NR'S0 2 -R wherein R is alkyl and R' is hydrogen or alkyl.
  • Aminocarbonyloxyalkyl or “carbamylalkyl” means a group of the formula -R-0-C(0)-NR'R” wherein R is alkylene and R', R" each independently is hydrogen or alkyl as defined herein.
  • Alkynylalkoxy means a group of the formula -O-R-R' wherein R is alkylene and R' is alkynyl as defined herein.
  • Aryl means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring.
  • the aryl group can be optionally substituted as defined herein.
  • aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxy
  • Arylsulfonyl means a group of the formula -S0 2 -R wherein R is aryl as defined herein.
  • Aryloxy means a group of the formula -O-R wherein R is aryl as defined herein.
  • Alkyloxy means a group of the formula -O-R-R" wherein R is alkylene and R' is aryl as defined herein.
  • Carboxy or “hydroxycarbonyl”, which may be used interchangeably, means a group of the formula -C(0)-OH.
  • Cyanoalkyl means a moiety of the formula -R'-R", where R' is alkylene as defined herein and R" is cyano or nitrile.
  • Cycloalkyl means a monovalent saturated carbocyclic moiety consisting of mono- or bicyclic rings. Particular cycloalkyl are unsubstituted or substituted with alkyl. Cycloalkyl can optionally be substituted as defined herein. Unless defined otherwise, cycloalkyl may be optionally substitued with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino.
  • cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated (cycloalkenyl) derivatives thereof.
  • Cycloalkenyl means a cycloalkyl as defined herein that includes at least one double bond or unsaturation.
  • exemplary cycloalkenyl include cyclohexenyl, cyclopentenyl, cyclobutenyl and the like.
  • Cycloalkylalkyl means a moiety of the formula -R'-R", where R' is alkylene and R" is cycloalkyl as defined herein.
  • Cycloalkylalkoxy means a group of the formula -O-R-R' wherein R is alkylene and R' is cycloalkyl as defined herein.
  • Cycloalkylcarbonyl means a moiety of the formula -C(0)-R, wherein R is cycloalkyl as defined herein.
  • Cs ⁇ cycloalkyl-C ! ⁇ alkyl-carbonyl means a moiety of the formula -C(0)-R, wherein R is cycloalkylalkyl as defined herein.
  • Cyanoalkylcarbonyl means a moiety of the formula -C(0)-R-R' , wherein R is alkylene as defined herein and R' is cyano or nitrile.
  • N-Cyano-aminocarbonyl means a moiety of the formula -C(0)-NHR, wherein R is cyano or nitrile.
  • N-Cyano-N-alkyl-aminocarbonyl means a moiety of the formula -C(0)-NRR' -R, wherein R' is alkyl as defined herein and R is cyano or nitrile.
  • Cycloalkylsulfonyl means a group of the formula -S0 2 -R wherein R is cycloalkyl as defined herein.
  • Cycloalkylalkylsulfonyl means a group of the formula -S0 2 -R wherein R is cycloalkylalkyl as defined herein.
  • Forml means a moiety of the formula -C(0)-H.
  • Heteroaryl means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring.
  • the heteroaryl ring may be optionally substituted as defined herein.
  • heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl
  • Heteroarylalkyl or “heteroaralkyl” means a group of the formula -R-R' wherein R is alkylene and R' is heteroaryl as defined herein.
  • Heteroarylsulfonyl means a group of the formula -S0 2 -R wherein R is heteroaryl as defined herein.
  • Heteroaryloxy means a group of the formula -O-R wherein R is heteroaryl as defined herein.
  • Heteroaralkyloxy means a group of the formula -O-R-R" wherein R is alkylene and R' is heteroaryl as defined herein.
  • halo refers to a substituent fluoro, chloro, bromo, or iodo.
  • Haloalkyl means alkyl as defined herein in which one or more hydrogen has been replaced with same or different halogen.
  • exemplary haloalkyls include -CH 2 C1,
  • Haloalkoxy means a moiety of the formula -OR, wherein R is a haloalkyl moiety as defined herein.
  • An exemplary haloalkoxy is difluoromethoxy.
  • Heterocycloamino means a saturated ring wherein at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.
  • Heterocyclyl means a monovalent saturated moiety, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (chosen from nitrogen, oxygen or sulfur).
  • the heterocyclyl ring may be optionally substituted as defined herein.
  • Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, morpholinyl,
  • thiomorpholinyl azepinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl and the like.
  • heterocyclyl may be optionally substituted as defined herein.
  • Heterocyclylalkyl means a moiety of the formula -R-R' wherein R is alkylene and R' is heterocyclyl as defined herein.
  • Heterocyclyloxy means a moiety of the formula -OR wherein R is heterocyclyl as defined herein.
  • Heterocyclylalkoxy means a moiety of the formula -OR-R' wherein R is alkylene and R' is heterocyclyl as defined herein.
  • Hydroalkoxy means a moiety of the formula -OR wherein R is hydroxyalkyl as defined herein.
  • Haldroxyalkylamino means a moiety of the formula -NR-R' wherein R is hydrogen or alkyl and R' is hydroxyalkyl as defined herein.
  • Haldroxyalkylaminoalkyl means a moiety of the formula -R-NR'-R" wherein R is alkylene, R' is hydrogen or alkyl, and R" is hydroxyalkyl as defined herein.
  • Haldroxycarbonylalkyl or “carboxyalkyl” means a group of the formula -R-(CO)-OH where R is alkylene as defined herein.
  • Hydroxycarbonylalkoxy means a group of the formula -0-R-C(0)-OH wherein R is alkylene as defined herein.
  • Hydrocarbonylalkoxy means a moiety of the formula -C(0)-R-R' , wherein R is alkylene as defined herein and R' is hydroxy.
  • Haldroxyalkyloxycarbonylalkyl or “hydroxyalkoxycarbonylalkyl” means a group of the formula -R-C(0)-0-R-OH wherein each R is alkylene and may be the same or different.
  • Hydroalkyl means an alkyl moiety as defined herein, substituted with one or more, for example, one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group.
  • Representative examples include, but are not limited to, hydroxymethyl,
  • Hydrocycloalkyl means a cycloalkyl moiety as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been replaced with a hydroxy substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.
  • a 1-oxo-ethyl group is an acetyl group.
  • Alkoxy hydroxyalkyl and "hydroxy alkoxyalkyl”, which may be used interchangeably, means an alkyl as defined herein that is substituted at least once with hydroxy and at least once with alkoxy.
  • Alkoxy hydroxyalkyl and hydroxy alkoxyalkyl thus encompass, for example, 2-hydroxy-3- methoxy-propan-l-yl and the like.
  • Rea'Or “ureido” means a group of the formula -NR'-C(0)-NR"R"' wherein R', R" and R'" each independently is hydrogen or alkyl.
  • “Carbamate” means a group of the formula -0-C(0)-NR'R" wherein R' and R" each
  • Carboxy means a group of the formula -0-C(0)-OH.
  • Sulfonamido means a group of the formula -S0 2 -NR'R" wherein R', R" and R'" each independently is hydrogen or alkyl.
  • cycloalkyl or heterocyclyl moiety means that such moiety may be unsubstituted (i.e., all open valencies are occupied by a hydrogen atom) or substituted with specific groups as related herein.
  • leaving group means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions.
  • Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.
  • “Modulator” means a molecule that interacts with a target. The interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein.
  • Disease and Disease state means any disease, condition, symptom, disorder or indication.
  • Inert organic solvent or “inert solvent” means the solvent is inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, ⁇ , ⁇ -dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, ferf-butanol, dioxane, pyridine, and the like.
  • the solvents used in the reactions of the present invention are inert solvents.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound.
  • Protecting group means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon the protective groups to block reactive nitrogen and/or oxygen atoms present in the reactants.
  • the terms "amino-protecting group” and “nitrogen protecting group” are used interchangeably herein and refer to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures.
  • Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl
  • Solidvates means solvent additions forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H 2 0, such combination being able to form one or more hydrate.
  • Arthritis means a disease or condition that causes damage to joints of the body and pain associated with such joint damage. Arthritis includes rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, and other arthritic conditions.
  • Respiratory disorder refers to, without limitation, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and the like.
  • COPD chronic obstructive pulmonary disease
  • Subject means mammals and non-mammals. Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "subject” does not denote a particular age or sex.
  • “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state.
  • the “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.
  • Treating" or “treatment” of a disease state includes, inter alia, inhibiting the disease state, i.e. , arresting the development of the disease state or its clinical symptoms, and/or relieving the disease state , i. e. , causing temporary or permanent regression of the disease state or its clinical symptoms.
  • treating when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
  • the atoms represented in the structures herein are intended to encompass all naturally occurring isotopes of such atoms.
  • the hydrogen atoms represented herein are meant to include deuterium and tritium
  • the carbon atoms are meant to include C 13 and C 14 isotopes.
  • One or more carbon atom(s) of a compound of the invention may be replaced by a silicon atom(s), and it is contemplated that one or more oxygen atom(s) of a compound of the invention may be replaced by a sulfur or selenium atom(s).
  • A is a group selected from:
  • p is from 0 to 3;
  • s is from 0 to 3 ;
  • R is: hydrogen; or Ci- 6 alkyl which may be unsubstituted or substituted one or more times with halo;
  • each R e is independently: hydrogen; Ci_ 6 alkyl; halo; Ci_ 6 alkoxy; or cyano; wherein the Ci- 6 alkyl moieties may be unsubstituted or substituted one or more times with halo.
  • p 0.
  • p is 1.
  • p is 2.
  • s is 0.
  • s is 1.
  • s is 2.
  • each R e is independently: hydrogen; or halo.
  • each R e is independently: hydrogen; or fluoro.
  • R e is hydrogen
  • R e is Ci_ 6 alkyl.
  • R e is halo. In certain embodiments of Formula I, R e is Ci- 6 alkoxy.
  • R e is cyano
  • R e is halo-Ci_ 6 alkyl.
  • p is from 0 to 3;
  • q is from 0 to 3;
  • s is from 0 to 3;
  • Het is heteroaryl selected from: oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; pyrazolyl;triazolyl; oxadiazolyl; thiadiazolyl; pyridinyl; pyrimidinyl; pyrazinyl; or imidazolyl;
  • A is: -CH(CH 3 )-NR a -CH 2 -; -CH(CH 3 )-NR a -C(0)-; or -CH(CH 3 )-NR a -C(0)-CH 2 -;
  • R is: hydrogen; or Ci_ 6 alkyl which may be unsubstituted or substituted one or more times with halo;
  • each R 9 is independently: Ci_ 6 alkyl; halo; Ci_ 6 alkoxy; or cyano; wherein the Ci_ 6 alkyl moieties may be unsubstituted or substituted one or more times with halo;
  • each R 10 is independently: Ci- 6 alkyl; hydroxy; oxo; cyano; halo; hydroxy-Ci- 6 alkyl; or C i_ 6 alkoxy-C i- 6 alkyl ;
  • R a is: hydrogen; or Ci- 6 alkyl and
  • each R e is independently:
  • Ci- 6 alkyl moieties may be unsubstituted or substituted one or more times with halo.
  • the compound is selected from:
  • p is from 0 to 2. In certain embodiments of Formula ] I. P is O or 1
  • s is 1.
  • s is 2.
  • s is O or 1
  • A is -CH(CH 3 )-NR a -CH 2 -
  • A is -CH(CH 3 )-NR a -C(0)-;
  • A is -CH(CH 3 )-NR a -C(0)-CH 2 -;
  • Het is: oxadiazolyl; or thiadiazolyl
  • Het is imidazolyl.
  • Het is pyrazolyl
  • Het is isoxazolyl.
  • Het is oxazolyl
  • Het is thiazolyl
  • Het is oxadiazolyl.
  • Het is triazolyl
  • Het is tetrazolyl.
  • Het is thiophenyl
  • Het is furanyl
  • Het is pyridinyl
  • Het is pyrimidinyl
  • Het is pyridazinyl
  • R is hydrogen
  • R 3 is Ci_ 6 alkyl.
  • each R 9 is independently: Ci- 6 alkyl; halo; or halo-Ci_ 6 alkyl
  • Formula R is Ci_ 6 alkyl.
  • Formula R 9 is Ci_ 6 alkoxy.
  • Formula R 9 is halo-Ci_ 6 alkyl.
  • each R 9 is independently: fluoro; chloro; or trifluoromethyl.
  • R is: Ci_ 6 alkyl; hydroxy; oxo; or hydroxy-C i _ 6 alkyl .
  • R 10 is hydroxy
  • R 10 is oxo.
  • R 10 is cyano
  • R 10 is halo.
  • R 10 is hydroxy-Ci_ 6 alkyl.
  • R 10 is Ci- 6 alkoxy-Ci_ 6 alkyl.
  • each R e is independently:
  • Ci- 6 alkyl hydrogen; Ci- 6 alkyl; halo; or cyano; wherein the Ci- 6 alkyl moieties may be unsubstituted or substituted one or more times with halo;
  • each R e is independently: hydrogen; Ci_ 6 alkyl; halo; or halo-Ci_ 6 alkyl.
  • each R e is independently: hydrogen; Ci_
  • each R e is independently: hydrogen; or halo. In certain embodiments of Formula II, each R e is independently: hydrogen; or fluoro.
  • R e is hydrogen
  • R e is Ci_ 6 alkyl.
  • R e is halo
  • R e is Ci- 6 alkoxy.
  • R e is cyano
  • R e is halo-Ci_ 6 alkyl.
  • R f is: Ci- 6 alkyl; halo; oxo; hydroxy; acetyl; or Ci_ 6 alkoxy.
  • the invention also provides a method for treating a disease or condition mediated by or otherwise associated with the RORc receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • the disease may be arthritis such as rheumatoid arthritis or osteoarthritis.
  • the disease may be asthma or COPD.
  • the disease may be psoriasis.
  • the disease may be muscular distrophy.
  • the starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagentsor Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions , Wiley & Sons: New York, 1991, Volumes 1-40.
  • the following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.
  • the starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
  • the reactions described herein may be conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about -78 °C to about 150 °C, for example, from about 0 °C to about 125 °C, or conveniently at about room (or ambient) temperature, e.g., about 20 °C.
  • Scheme A illustrates one synthetic procedure usable to prepare specific compounds of formula I, wherein LG is a leaving group such as halo, sulfonate, or the like, and m, n, p, q, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R b and R c are as defined herein.
  • LG is a leaving group such as halo, sulfonate, or the like
  • m, n, p, q, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R b and R c are as defined herein.
  • step 1 of Scheme A alkyl amine a is reacted with benzyl sulfonyl chloride b to form sulfonamide compound c.
  • the reaction of step 1 may be carried out in a polar aprotic solvent such as THF or methylene chloride, and in the presence of a tertiary amine base or weak base such as potassium carbonate.
  • the leaving group of compound a may be bromo in certain embodiments.
  • the chloro group of compound b may in certain embodiments be replaced by other halo or leaving group.
  • a cyclization reaction is carried out in step 2 to afford thiazinane compound d.
  • the cyclization may be achieved in the presence of a strong base such as an alkyl lithium reagent, using polar aprotic solvent under anhydrous conditions.
  • step 3 thiazinane compound c is reacted with aryalkyl halide compound e to yield aralkyl thiazinane f.
  • the reaction of step 3 may be carried out in the presence of a strong base such as sodium hydride under anhydrous polar aprotic solvent conditions.
  • the bromo groups of compound e may be replaced by other suitable leaving groups used in the art.
  • Thiazinane compound f may then be reacted with oxoethyl zinc halide reagent g in step 4 to provide ester compound h.
  • This reaction may be carried out in the presence of suitable palladium catalyst under polar aprotic conditions in a solvent such as dry
  • step 5 ester compound h is reacted with hydrazine to yield the corresponding hydrazide compound i.
  • step 6 hydrazide compound is reacted with acyl halide reagent ⁇ to afford an acyl hydrazide compound k.
  • step 7 a cyclization is carried out to form an oxadiazole group, resulting in the compound 1, whihch is a compound of formula I in accordance with the invention.
  • reagent g may be replaced by the corresponding thionoester to provide a thiadiazole group in the final compound.
  • the group R a may be replaced by an alkyl group, or may omitted from reagent g and introduced (if desired) in a later step.
  • the group R 10 may omitted from acyl reagent ⁇ and, if desired, introduced in a later step.
  • Scheme B below shows another synthetic procedure usable to prepare specific compounds of formula I, wherein TBS is tri-(tert-butyl)-silyl, and m, n, p, q, X ⁇ X , X", X , Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 and R 10 are as defined herein.
  • step 1 of Scheme B tri-(tert-butyl)-slilyloxy amine m is reacted with benzyl sulfonyl chloride b, as described above with reference to Scheme A, to form sulfonamide compound n.
  • the tri-(tert-butyl)-slilyloxy group may be replaced with other leaving groups.
  • step 2 sulfonamide compound n is reacted with iodochloromethane to provide an alkenylsulfonamide compound o. This reaction may be achieved in the presence of a strong base such as an alkyl lithium reagent, using polar aprotic solvent such as THF under anhydrous conditions.
  • iodochloromethane may be replaced with other methylene reagents.
  • step 3 a cyclization reaction is affected to provide oxathiazepane compound p_.
  • the cyclization may be carried out in the presence of an amine base under polar aprotic solvent conditions.
  • step 4 oxathiazepane compound p_ is reacted with aryalkyl halide compound e to yield aralkyl oxathiazepane compound q, in the manner described above with reference to Scheme A.
  • Steps 5-8 may then be carried out in the manner described above for steps 4-7 of Scheme A. Briefly, oxathiazepane compound q is reacted with zinc halide reagent g in step 5 to provide ester compound r, which is then reacted with hydrazine in step 6 to give the
  • Hydrazide compound s may then b acylated in step 7 to make compound t, followed by ring closure in step 8, to afford sultam compound u, which is a compound of formula I in accordance with the invention.
  • the invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a
  • the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, for example 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved.
  • One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.
  • Compounds of the invention may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous)
  • administration or in a form suitable for administration by inhalation or insufflation.
  • a particular manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
  • a compound or compounds of the invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages.
  • the pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use.
  • Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
  • the compounds of the invention may be formulated in a wide variety of oral administration dosage forms.
  • the pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component.
  • the pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
  • the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets may contain from about one (1) to about seventy (70) percent of the active compound.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation” is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.
  • liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations.
  • Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia.
  • Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents.
  • Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
  • Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the compounds of the invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
  • oily or nonaqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
  • the compounds of the invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the compounds of the invention may be formulated for administration as suppositories.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
  • the compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the subject compounds may be formulated for nasal administration.
  • the solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray.
  • the formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
  • the compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
  • the compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example,
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by a metered valve.
  • the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatine or blister packs from which the powder may be administered by means of an inhaler.
  • formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
  • the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial.
  • Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support.
  • the compound of interest can also be combined with a penetration enhancer, e.g., Azone (l-dodecylazacycloheptan-2-one).
  • Sustained release delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection.
  • the subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.
  • the pharmaceutical preparations may be in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the compounds of the invention are useful for treatment of immune disorders generally.
  • the compounds may be used for treatment of arthritis, including rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, and other arthritic conditions.
  • the compounds may be used for treatment of respiratory disorders such as chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and the like.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • the compounds may be used for treatment of gastrointestinal disorder ("GI disorder”) such as
  • IBS Irritable Bowel Syndrome
  • IBD Inflammatory Bowel Disease
  • biliary colic and other biliary disorders renal colic
  • renal colic diarrhea-dominant IBS
  • pain associated with GI distension and the like.
  • the compounds may be used for treatment of psoriasis, muscular sclerosis, Sjogren' s disease, lupus, and pulmonary fibrosis.
  • Method A Compounds were analysed using the following conditions: Experiments were performed on a Waters ZMD single quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC system with UV diode array detector and 100 position autosampler. The spectrometer has an electrospray source operating in positive and negative ion mode. This system uses a Phenomenex Luna 3 ⁇ CI 8(2) 30 x 4.6 mm column at ambient temperature and a 2.0 mL / minute flow rate.
  • the initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 min followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 min. This was maintained for 1 min before returning to 95% solvent A and 5% solvent B over the next 0.5 min. Total run time was 6 min.
  • Method B Compounds were analysed using the following conditions: Experiments were performed on a Waters Micromass ZQ2000 quadrupole mass spectrometer linked to a Waters Acquity UPLC system with a PDA UV detector.
  • the spectrometer has an electrospray source operating in positive and negative ion mode.
  • This system uses an Acquity BEH CI 8 1.7 ⁇ 100 x 2.1 mm column, maintained at 40 °C or an Acquity BEH Shield RP18 1.7 ⁇ 100 x 2.1 mm column, maintained at 40 °C and a 0.4 mL / minute flow rate.
  • the initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.4 min followed by a gradient up to 5% solvent A and 95% solvent B over the next 5.6 min. This was maintained for 0.8 min before returning to 95% solvent A and 5% solvent B over the next 1.2 min. Total run time was 8 min.
  • 1H NMR spectra were recorded at ambient temperature or at 80 °C where indicated using one of the following machines: Varian Unity Inova (400 MHz) spectrometer with a triple resonance 5mm probe, Bruker Avance DRX 400 (400 MHz) spectrometer with a triple resonance 5mm probe, a Bruker Avance DPX 300 (300 MHz) equipped with a standard 5 mm dual frequency probe for detection of 1H and 13C, Bruker Fourier 300MHz system equipped with a standard 5 mm probe, a Bruker AVIII (400 MHz) using a BBI Broad Band Inverse 5 mm probe, or a Bruker AVIII (500 MHz) using a QNP (Quad Nucleus detect) 5 mm probe.
  • Varian Unity Inova 400 MHz
  • Bruker Avance DRX 400 400 MHz
  • a triple resonance 5mm probe a Bruker Avance DPX 300 (300 MHz) equipped with a standard 5 mm dual frequency
  • Microwave reactions were carried out using a Biotage ® Initiator ® in vials appropriate to the scale of the reaction and at the temperature and time described in the experimental details.
  • Purification Equipment :
  • Reverse Phase High Pressure Liquid Chromatography was used to purify compounds where indicated. Separation using gradient elution on a Phenomenex Gemini CI 8 column (250 x 21.2 mm, 5 micron) as stationary phase and using mobile phase indicated, operating at a 18 mL/min flow rate using a Gilson UV/Vis -155 dual channel detector and Gilson GX-271 automated liquid handler.
  • Phase separator cartridges are supplied by Biotage® as Isolute® phase separator cartridges.
  • Step 2 Benzyl N-r(2.S')-4-hydroxybutan-2-yllcarbamate and Benzyl N-r(2i?)-4-hydroxybutan-2- yllcarbamate
  • Step 3 (3i?)-3-Aminobutan-l-ol and (3 ⁇ )-3-Aminobutan-l-ol
  • Step 1 (i?)-3-(Phenylmethylsulfonamido)butyl phenylmethanesulfonate
  • Step 2 (i?)-N-(4-Chlorobutan-2-yl)-l -phenylmethanesulfonamide To the crude (ii)-3-(phenylmethylsulfonamido)butyl phenylmethanesulfonate (23.6 mmol) was added sodium chloride (984 mg, 16.8 mmol) and dimethylformamide (37 mL) and the reaction was stirred at 80 °C for 16 hours.
  • N-(2-bromoethyl)(4-fluorophenyl)methanesulfonamide was also made using the above procedure, replacing phenylmethanesulfonyl chloride with 4-fluoro-phenylmethanesulfonyl chloride.
  • X H NMR 300 MHz, CDC1 3 ) ⁇ 7.43-7.38 (m, 2H), 7.13-7.07 (m, 2H), 4.62 (br s, 1H), 4.26 (s, 2H), 3.41-3.32 (m, 4H).
  • N-(3-bromopropyl)(4-fluorophenyl)methanesulfonamide was prepared using the above procedure.
  • 1H NMR 300 MHz, CDC1 3 ) ⁇ 7.42-7.37 (m, 2H), 7.13-7.07 (m, 2H), 4.26 (m, 1H), 4.24 (s, 2H), 3.46-3.42 (m, 2H), 3.20-3.16 (m, 2H), 2.05-2.00 (m, 2H).
  • Step 1 N-(2-((Tert-butyldimethylsilyl)oxy)ethyl)- 1 -phenylmethanesulfonamide
  • Step 2 N-(2-((Tert-butyldimethylsilyl)oxy)ethyl)- 1 -phenylethenesulfonamid
  • Step 1 r2,5-Difluoro-4-((3 ⁇ ',6i?)-3-methyl-l ,l-dioxo-6-phenyl-llambda*6*-ri,21thiazinan-2- ylmethyP-phenyll-acetic acid
  • Step 2 r2,5-Difluoro-4-((3 ⁇ ',6i?)-3-methyl-l,l-dioxo-6-phenyl-llambda*6*-ri,21thiazinan-2- ylmethyP-phenyll-acetic acid methyl ester
  • Step 1 Diazo-r2,5-difluoro-4-((3 ⁇ ,6i?)-3-methyl-l J-dioxo-6-phenyl-llambda*6*-ri,21thiazinan- 2-ylmethyl)-phenyll-acetic acid methyl ester
  • Step 2 r2,5-Difluoro-4-((3 ⁇ ',6i?)-3-methyl-lJ-dioxo-6-phenyl-llambda*6*-ri,21thiazinan-2- ylmethyl)-phenyll-oxetan-3-yl-acetic acid methyl ester
  • Step 1 3-Fluoro-4-rL2,41triazol-4-yl-piperidine-l-carboxylic acid tert-butylester
  • Step 3 (35,6R)-2-rr2,5-difluoro-4-r(35,4R)-3-fluoro-4-(l ,2,4-triazol-4-yl)-l- piperidyllphenyllmethyll-3-methyl-6-phenyl-thiazinane 1,1-dioxide and (3£,6 ⁇ )-2- ⁇ 2,5- difluoro-4 (3i? ⁇ )-3-fluoro-4-(l,2 ⁇ riazol-4-yl) -piperidyllphenyllmethyll-3-methyl-6- phenyl-thiazinane 1,1 -dioxide
  • Examples 5 and 6 (2.S')-2-r2,5-difluoro-4-rr(3 ⁇ ',6i?)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yllmethyllphenyll-3-(oxetan-3-yl)propanamide and (2i?)-2-r2,5-difluoro-4-rr(3£,6i?)-3-methyl- l,l-dioxo-6-phenyl-thiazinan-2-yllmethyllphenyll-3-(oxetan-3-yl)propanamide and (2i?)-2-T2,5- difluoro-4-rr(3 ⁇ ',6i?)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yllmethyllphenyll-3-(oxetan-3- yPpropanamide
  • Example 7 l-r2,5-difluoro-4-rr(3 ⁇ ',6i?)-3-methyl-lJ-dioxo-6-phenyl-thiazinan-2- yllmethyllphenyll-3-hydroxy-3-(trifluoromethyl)cyclobutanecarboxamide
  • Step 4 l-(2,5-Difluoro-4-methylphenyl)-3,3-dimethoxycyclobutanecarbonitrile
  • Step 5 l-(2,5-Difluoro-4-methylphenyl)-3,3-dimethoxycyclobutanecarboxylic acid
  • a solution of l-(2,5-difluoro-4-methylphenyl)-3,3-dimethoxycyclobutanecarbonitrile (6.7 g, 25.1 mmol) and KOH (50% aqueous, 15 g) in n-BuOH (30 ml) were heated at 125 °C for 16 h. The reaction mixture was concentrated under reduced pressure. Water (100 mL) was added and extracted with EtOAc (2 x 100 mL).
  • Step 6 Methyl l-(2,5-difluoro-4-methylphenyl)-3,3-dimethoxycyclobutane-l- carboxylate
  • Step 7 l-(4-Bromomethyl-2,5-difluoro-phenyl)-3,3-dimethoxy-cyclobutanecarboxylic acid methyl ester
  • Step 8 l-r2.5-Difluoro-4-((3 t S'.6 ⁇ )-3-methyl-l.l-dioxo-6-phenyl-llambda*6*-ri.21thiazinan-2- ylmethyl)-phenyll-3,3-dimethoxy-cyclobutanecarboxylic acid methyl ester
  • Step 9 l-r2,5-Difluoro-4-((3 t S',6 ⁇ )-3-methyl-l,l-dioxo-6-phenyl-llambda*6*-ri,21thiazinan-2- ylmethyl)-phenyll-3-oxo-cyclobutanecarboxylic acid methylester
  • Step 10 l-r2,5-Difluoro-4-((3 t S',6 ⁇ )-3-methyl-l,l-dioxo-6-phenyl-llambda*6*-ri,21thiazinan-2- ylmethyl)-phenyll-3-hydroxy-3-trifluoromethyl-cyclobutanecarboxylic acid methyl ester
  • Step 11 trans 1 2,5-Difluoro-4-((35,6R)-3-methyl-l J-dioxo-6-phenyl-llambda*6*-ri,2 lthiazinan-2-ylmethyl)-phenyll-3-hydroxy-3-trifluoromethyl-cyclobutanecarboxylic acid methyl esters
  • aqueous phase was acidified using 1 N HC1, extracted with EtOAc, dried (Na 2 S0 4 ), filtered and concentrated in vacuo to provide cis l-[2,5-difluoro-4-((3.S',6ii)-3-methyl-l ,l-dioxo-6-phenyl-llambda*6*-[l,2]thiazinan- 2-ylmethyl)-phenyl]-3-hydroxy-3-trifluoromethyl-cyclobutane carboxylate.
  • Step 12 l-r2,5-Difluoro-4-((3 t S',6 ⁇ )-3-methyl-l,l-dioxo-6-phenyl-llambda*6*-ri,21thiazinan-2- ylmethyl)-phenyll-3-hydroxy-3-trifluoromethyl-cyclobutanecarboxylic acid
  • Step 13 l-r2,5-difluoro-4-rr(3 ⁇ ',6i?)-3-methyl-l J-dioxo-6-phenyl-thiazinan-2- yllmethyllphenyll-3-hydroxy-3-(trifluoromethyl)cvclobutanecarboxamide
  • Example 8 Methyl 4-r2,5-difluoro-4-rr(3 ⁇ ',6i?)-3-methyl-lJ-dioxo-6-phenyl-thiazinan-2- yllmethyllphenylltetrahydropyran-4-carboxylate
  • Step 1 4-(3-Huoro-4-(((35.6R)-3-metfayl-l J-dioxido-6-phenyl-1.2-t azinan-2
  • Step 2 N-(Cvclopropylmethyl)-4-r3-fluoro-4-rr(3 ⁇ ',6i?)-3-methyl-lJ-dioxo-6-phenyl-thiazinan- 2-yllmethyllphenylltetrahydropyran-4-carboxamide
  • a vial was charged with the product from step 1 (50 mg, 0.11 mmol)
  • Example 10 1- r2,5-Difluoro-4- ⁇ (3S,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yllmethyllphenyll-N-(isoxazol-4-ylmethyl)ethanamine
  • Step 1 N-(l-(4-(((fer?-Butyldimethylsilyl)oxy)methyl)-2,5-difluorophenyl)ethyl)-2- methylpropane-2-sulfinamide
  • Step 2 N-(l-(2,5-Difluoro-4-(hydroxymethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide To a solution of the product from step 1 (7.7 g, 19 mmol) in THF (100 mL) was added
  • Step 3 N-(l-(4-(Chloromethyl)-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Step 4 N-(l-(2,5-Difluoro-4-(((3 t S',6 ⁇ )-3-methyl-l,l-dioxido-6-phenyl-l,2-thiazinan-2- yl)methyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Step 5 1 -(2,5 -Difluoro-4-(((3 ⁇ ',6i?)-3-methyl- 1 , 1 -dioxido-6-phenyl- 1 ,2-thiazinan-2- yl)methyl)phenyl)ethan- 1 -aminium chloride
  • Step 6 l-r2,5-Difluoro-4-rr(3£,6i?)-3-methyl-l J-dioxo-6-phenyl-thiazinan-2-yllmethyllphenyll- N-(isoxazol-4-ylmethyl)ethanamine
  • Step 1 tert-Butyl 2-diazo-2-(2,5-difluoro-4-(((3 t S',6i?)-3-methyl-l,l-dioxido-6-phenyl-l,2- thiazinan-2-yl)methyl)phenyl)acetate
  • Step 2 fer/-Butyl 2-(2,5-difluoro-4-(((3 ⁇ ',6i?)-3-methyl-l J-dioxido-6-phenyl-l,2-thiazinan-2- yl)methyl)phenyl)-2-phenylacetate
  • Step 3 (3 ⁇ ,6i?)-2-(2,5-Difluoro-4-(2-hydroxy-l-phenylethyl)benzyl)-3-methyl-6-pheny thiazinane 1,1 -dioxide
  • step 2 To a solution of the product of step 2 (490 mg, 0.90 mmol) in THF (5 mL) at 0 °C was added lithium aluminum hydride (1.4 mL, 2.0 M in THF) and the reaction was stirred at 0 °C for 1 h. The reaction was quenched with 50% aqueous potassium sodium tartrate, extracted with Et 2 0, dried over MgS0 4 , filtered, and purified by silica gel column chromatography to give the title compound (213 mg, 50% yield).
  • Example 13 In vitro RQRc Ligand Binding Assay This assay was used to determine a compound's potency in inhibiting activity of RORc by determining, Ki app , IC 50 , or percent inhibition values. Consumables used in this Example are shown in Table 5 below.
  • NBS Nonspecific binding
  • TB Total Binding
  • No R No Receptor
  • DMSO as for compounds above, then diluted in Assay Buffer to give a final concentration of 5 uM.
  • Assay Buffer For 25-hydroxycholesterol in 25% DMSO/75% Assay Buffer; 10 uL per well was used for NSB samples.
  • Wells for Total Binding and No Receptor sample determination contained 10 uL of 25% DMSO/75% Assay Buffer per well.
  • 25-[ 3 H]hydroxycholesterol was diluted in Assay Buffer to obtain 15 nM and vortex to mix. Add 20 uL to all wells to reach 6 nM final concentration in the assay.
  • the optimal concentration for RORc receptor was found to be 0.6 ug/mL.
  • Stock receptor solution was diluted in assay buffer to obtain 1.5 ug/mL in Assay Buffer. 20 uL was added to all wells.
  • Assay plates were 96-well polypropylene V-bottom plates. 10 uL of 5x compound in
  • Buffer was added to all wells. 20 uL of 1.5 ug/mL RORc receptor was added to wells (or 40 uL Assay
  • test ligand were mixed in coregulator buffer D (Invitrogen PV4420) containing 5 niM DTT and added to the plate at twice their final concentrations in a volume of 8 microL. Test ligands at 2x the final concentration were then added to the wells in 8 L of coregulator buffer D containing 5 niM DTT and 4% DMSO.
  • Final incubations contained lx coregulator buffer D, 5 niM DTT, test ligand, 2% DMSO, 50 nM biotinyl-CPSSHSSLTERKHKILHRLLQEGSPS (American Peptide Company; Vista, CA), 2 nM Europium anti-GST (Cisbio 61GSTKLB), 12.5 nM streptavidin-D2 (Cisbio 610SADAB), 50 mM KF, and 10 nM of bacterially-expressed human RORc ligand binding domain protein containing an ⁇ -terminal 6xHis-GST-tag and residues 262-507 of Accession NP_005051. Ten test ligand concentrations were tested in duplicate.
  • the plate was read on an EnVision plate reader (PerkinElmer) following the Europium/D2 HTRF protocol (ex 320, em 615 and 665, 100 s lag time, 100 flashes, 500 ⁇ 8 window).
  • the time-resolved FRET signal at 665 nm was divided by that at 615 nm to generate the signal ratio of each well.
  • the signal ratio of wells containing RORc and peptide but no test ligand were averaged and set to 0% Effect while the signal ratios of the blank wells containing coactivator peptide but no RORc were averaged and set to -100% Effect.
  • RORc exhibits a basal (constitutive) signal in this assay and test ligands can increase or decrease the signal ratio relative to this basal signal level.
  • RORc agonists increase the signal ratio in this assay and result in a positive % Effect value.
  • Inverse agonists decrease the signal ratio, and result in a negative % Effect value.
  • the EC 50 value is the concentration of test compound that provides half-maximal effect (increased or decreased assay signal) and is calculated by Genedata Screener® software (Genedata; Basel, Switzerland) using the following equation:
  • S 0 equals the activity level at zero concentration of test compound
  • S inf is the activity level at infinite concentration of test compound
  • EC 50 is the concentration at which the activity reaches 50% of the maximal effect
  • c is the concentration in logarithmic units corresponding to the values on the x-axis of the dose-response curve plot
  • n is the Hill coefficient (the slope of the curve at the EC 50 ).
  • DBA/1 mice 8 to 10-week old male DBA/1 (DBA/lOlaHsd, Harlan Laboratories) mice are housed in a specific pathogen free (SPF) animal facility. Arthritis is induced by two injections of collagen subcutaneously in the base of the tail. The initial injection (on day 0) uses bovine type II collagen (2 mg/ml from Chondrex, Redmond, Wash.) emulsified in equal volume of CFA containing 4 mg/ml of M. tuberculosis (Chondrex). The CII booster injection on Day 29 is emulsified in incomplete Freund's adjuvant (IF A).
  • IF A incomplete Freund's adjuvant
  • Each animal receives 0.1 ml of emulsion by subcutaneous/intradermal injection in the tail 2 to 3 cm from the body of the mouse.
  • the booster injection site is in the vicinity of but different from the initial injection site and closer to the body of the animal.
  • OR- 1050 was formulated in HRC-6 as above. On weekdays, the animals receive two doses (a.m. and p.m.) of HRC-6 or 50 mg kg OR-1050 p.o. (2.5 mls kg). On weekends, a single dose of 100 mg kg is administered (5 mls/kg).
  • mice are observed daily for clinical symptoms of CIA based on the following qualitative scale. Each paw was examined individually and scored. Grade 0, normal; grade 1, mild but definite redness and swelling of the ankle or wrist, or apparent redness and swelling limited to individual digits, regardless of the number of affected digits; grade 2, moderate redness and swelling of ankle or wrist; grade 3, severe redness and swelling of the entire paw including digits; grade 4, maximally inflamed limb with involvement of multiple joints. To estimate cumulative disease severity for each animal, an area under the curve score is calculated for each animal by totaling the sum of the daily hind paw measurements betweens days 24 and 48.
  • mice aged 4-6 weeks belong to the C57BL/6 strain weighing 17-20 g.
  • Experimental autoimmune encephalomyelitis EAE is actively induced using 95% pure synthetic myelin oligodendrocyte glycoprotein peptide 35-55 (MOG 35 .55) (Invitrogen).
  • MOG 35 .55 myelin oligodendrocyte glycoprotein peptide 35-55
  • Invitrogen 95% pure synthetic myelin oligodendrocyte glycoprotein peptide 35-55
  • Each mouse is anesthetized and receives 200 ug of MOG 35 .55 peptide and 15 ug of Saponin extract from Quilija bark emulsified in 100 uL of phosphate-buffered saline.
  • a 25 uL volume is injected subcutaneously over four flank areas.
  • Mice are also intraperitoneally injected with 200 ng of pertussis toxin in 200 uL of PBS.
  • a compound of the invention is administered at selected doses.
  • Control animals receive 25 uL of DMSO.
  • Daily treatment extends from day 26 to day 36 post-immunization.
  • Clinical scores are obtained daily from day 0 post-immunization until day 60.
  • Clinical signs are scored using the following protocol: 0, no detectable signs; 0.5, distal tail limpness, hunched appearance and quiet demeanor; 1, completely limp tail; 1.5, limp tail and hindlimb weakness (unsteady gait and poor grip with hind limbs); 2, unilateral partial hind limb paralysis; 2.5, bilateral hind limb paralysis; 3, complete bilateral hindlimb paralysis; 3.5, complete hindlimb paralysis and unilateral forelimb paralysis; 4, total paralysis of hind limbs and forelimbs (Eugster et al., Eur J Immunol 2001, 31, 2302-2312).
  • Inflammation and demyelination may be assessed by histology on sections from the CNS of EAE mice. Mice are sacrificed after 30 or 60 days and whole spinal cords are removed and placed in 0.32 M sucrose solution at 4° C. overnight. Tissues are prepared and sectioned. Luxol fast blue stain is used to observe areas of demyelination. Haematoxylin and eosin staining is used to highlight areas of inflammation by darkly staining the nuclei of mononuclear cells. Immune cells stained with H&E are counted in a blinded manner under a light microscope. Sections are separated into gray and white matter and each sector is counted manually before being combined to give a total for the section. T cells are immunolabeled with anti-CD3+ monoclonal antibody. After washing, sections are incubated with goat anti-rat HRP secondary antibody. Sections are then washed and counterstained with methyl green.
  • mice are anesthetized with isoflurane and injected with Freund's Incomplete Adjuvant containing 1 mg/niL neuronal antigen (e.g. myelin basic protein, myelin oligodendrocyte glycoprotein, proteolipid protein) and 4 mg/niL mycobacterium tuberculosis at two sites on the back on day 0 of this study.
  • a compound of interest is then dosed daily in a sub-cutaneous, intra- peritoneally, or oral manner from day 0 until the end of study at an efficacious dose. Daily observations of degree of paralysis are taken as measures of efficacy.
  • SCID mice The severe, combined immunodeficient (SCID) mouse model can be used to evaluate the efficacy of compounds for treating psoriasis in humans (Boehncke, Ernst Schering Res Found Workshop 2005, 50, 213-34; and Bhagavathula et al., J Pharmacol Expt'l Therapeutics 2008, 324(3), 938-947). Briefly, SCID mice are used as tissue recipients. One biopsy for each normal or psoriatic volunteer (human) is transplanted onto the dorsal surface of a recipient mouse. Treatment is initiated 1 to 2 weeks after transplantation. Animals with the human skin transplants are divided into treatment groups. Animals are treated twice daily for 14 days. At the end of treatment, animals are photographed and then euthanized.
  • the transplanted human tissue along with the surrounding mouse skin is surgically removed and fixed in 10% formalin and samples obtained for microscopy. Epidermal thickness is measured. Tissue sections are stained with an antibody to the proliferation-associated antigen Ki-67 and with an anti-human CD3.sup.+ monoclonal antibody to detect human T lymphocytes in the transplanted tissue. Sections are also probed with antibodies to c-myc and beta-catenin. A positive response to treatment is reflected by a reduction in the average epiderma thickness of the psoriatic skin transplants. A positive response is also associated with reduced expression of Ki-67 in keratinocytes.
  • Balb/c mice (10 males/group) received daily topical IMQ (5% cream) on shaved back and right ear for 5 days as described above. Animals received oral dose of a representative compound or DMF (45 or 90 mg-eq MMF/kg twice daily) or vehicle from Day -5 to Day +5. Erythema score is the primary outcome measure. The Erythema score values of the compounds tested at an oral dose of 90 mg-eq MMF/kg BID for 10 days in male Balb/C mice are set forth in Table 3, below. The data shows that the compounds of the disclosure are equipotent to DMF.
  • Colonic mucosa samples are obtained and homogenized.
  • Proinflammatory mediators e.g., IL-lalpha, IL-lbeta, TNFalpha, PGE2, and PGF2alpha.
  • protein concentrations are quantified.
  • Each excised large intestine is histologically examined and the damage to the colon scored.
  • mice are divided into three groups of 40 animals each. These groups are then divided into four subgroups of 10 mice each as follows: (1) no treatment/air-exposed; (2) no treatment/smoke-exposed; (3) a first dose of test compound plus smoke- exposed; and (4) a second dose of test compound.
  • trolox equivalent antioxidant capacity is assessed at the end of the exposure in bronchoalveolar lavage fluid.
  • cytokines and chemokines are determined in bronchoalveolar lavage fluid using a commercial cytokine panel at 4 hours; and in the third group bronchoalveolar lavage fluid cell count is assessed at 24 hours.
  • the mice are exposed to either room air or to the smoke of three cigarettes/day, for 5 days/week, for 7 months.
  • mice Five groups of animals are used: (1) no treatment/air- exposed; (2) a first dose of a test compound plus air-exposed; (3) no treatment/smoke-exposed; (4) a second dose of the test compound plus smoke-exposed; and (5) the first dose of the test compound plus smoke exposed. Seven months after chronic exposure to room air or cigarette smoke, 5 to 12 animals from each group are sacrificed and the lungs fixed intratracheally with formalin. Lung volume is measured by water displacement. Lungs are stained. Assessment of emphysema includes mean linear intercept and internal surface area. The volume density of macrophages, marked immunohistochemically with anti-mouse Mac-3 monoclonal antibodies is determined by point counting.
  • a mouse is considered to have goblet cell metaplasia when at least one or more midsize bronchi/lung showed a positive periodic acid-Schiff staining for the determination of desmosine, fresh lungs are homogenized, processed, and analyzed by high-pressure liquid chromatography.
  • a single inhaled allergen challenge can induce an acute increase in airway responsiveness in some individuals and animal models.
  • repeated allergen inhalations have demonstrated more pronounced, consistent, and prolonged increases in airway responsiveness.
  • This mouse model of long- term repeated inhalations of allergen has been used to study the long term effect of allergic diseases in the lung, and to delineate the cells, mechanisms, molecules, and mediators involved in the induction of airway hyperresponsiveness of lung in humans.
  • Crystalline OVA is obtained from Pierce Chem. Co. (Rockford, 111.) aluminum potassium sulfate (alum) from Sigma Chem. Co. (St. Louis, Mo.), pyrogen-free distilled water from Baxter, Healthcare Corporation (Deerfield, 111.), 0.9% sodium chloride (normal saline) from Lymphomed (Deerfield, 111.) and Trappsol.TM.
  • HPB-L100 aqueous hydroxypropylbeta cyclodextrin; 45 wt/vol % aqueous solution) from Cyclodextrin Technologies Development, Inc. (Gainesville, Fla.).
  • the OVA 500 ug/ml in normal saline
  • the mixture pH 6.5 using 10 N NaOH
  • the selective 5-lipoxtgenase inhibitor Zileuton (N-[l-benzo[b]thien-2-ylethyl]-N-hydroxyurea; J. Pharmacol Exp Ther. 1991; 256: 929-937) is dissolved in Trappsol.TM. Histatek, Inc. (Seattle, Wash.) to provide the mast cell degranulation inhibitor, f-Met-Leu-Phe-Phe ("HK-X").
  • mice Female BALB/c Once (6-8 wk of age) receive an i.p. injection of 0.2 ml (100 ug) of OVA with alum on the different protocols of Standard (J. Exp Med. 1996; 184: 1483-1494). Mice are anesthetized with 0.2 ml i.p. of ketamine (0.44 mg/ml)/xylazine (6.3 mg/ml) in normal saline before receiving an intranasal (i.n.) dose of 100 ug OVA in 0.05 ml normal saline and an i.n. dose of 50 ug OVA in 0.05 ml normal saline separately on different days.
  • ketamine 0.44 mg/ml
  • xylazine 6.3 mg/ml
  • Two control groups are used: the first group receives normal saline with alum i.p. and normal saline without alum i.n. ; and the second group receives OVA with alum i.p., OVA without alum i.n., and normal saline, alone.
  • the trachea and left lung (the right lung may be used for bronchoalveolar lavage ("BAL") as described below) are obtained and fixed in 10% neutral formaldehyde solution at room temperature for about 15 h. After being embedded in paraffin, the tissues are cut into 5-um sections and processed with the different staining or immunolabling further. Discombe's eosinophil staining is used for counting the cell numbers with the counterstain of methylene blue. The eosinophil number per unit airway area (2,200 urn 2 ) is determined by morphometry (J. Pathol. 1992; 166: 395-404; Am Rev Respir Dis. 1993; 147:448- 456).
  • Airway mucus iss identified by the following staining method: methylene blue, hematoxylin and eosin, mucicarmine, alcian blue, and alcian blue/periodic acid-Schiff (PAS) reaction (Troyer, H., "Carbohydrates” in Principles and Techniques of Histochemistry, Little, Brown and Company, Boston, Mass., 1980: 89-121; Sheehan, D.
  • Mucin is stained with mucicarmine solution; metanil yellow counterstain is employed. Acidic mucin and sulfated mucosubstances are stained with alcian blue, pH 2.5; nuclear fast red counterstain is used. Neutral and acidic mucosubstances are identified by alcian blue, pH 2.5, and PAS reaction. The degree of mucus plugging of the airways (0.5-0.8 mm in diameter) is also assessed by morphometry. The percent occlusion of airway diameter by mucus iss classified on a semiquantitative scale from 0 to 4+. The histologic and morphometric analyses may be performed by individuals blinded to the protocol design.
  • pulmonary mechanics to intravenous infusion of methacholine may be determined in mice in vivo by a plethysmographic method as previously described (10, 1958; 192: 364-368; J. Appl. Physiol. 1988; 64: 2318-2323; J. Exp. Med. 1996; 184: 1483-1494).
  • BAL Bronchoalveolar lavage
  • Discombe's diluting fluid 0.05% aqueous eosin and 5% acetone (vol/vol) in distilled water; J. Exp. Med. 1970; 131 : 1271-1287) for 5-8 minutes, rinsed with water for 0.5 minutes, and counterstained with 0.07% methylene blue for 2 minutes.

Abstract

Compounds of the formula I: or a pharmaceutical salt thereof, wherein p, s, A, R3 and Re are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of inflammatory diseases such as arthritis.

Description

ARYL SULTAM DERIVATIVES AS RORc MODULATORS
FIELD OF THE INVENTION
The invention pertains to compounds that modulate the function of retinoid-receptor related orphan receptor RORc (RQRy) and use of such compounds for treatment of autoimmune diseases
BACKGROUND OF THE INVENTION
T helper 17 cells (Thl7) are interleukin (IL)-17 secreting CD4+ T cells involved in pathogenesis of autoimmune diseases such as rheumatoid arthritis, irritable bowel disease, psoriasis, psoriatic arthritis and spondyloarthridities. The retinoic acid-related orphan receptor γ (RORy or RORc) is recognized as a transcription factor necessary for Thl7 cell differentiation. RORc is an orphan member of the nuclear hormone receptor subfamily that includes RORa (RORa) and RORp (RORb). RORc controls gene transcription by binding to DNA as a monomer. Selective modulation of RORc has been proposed as a route to discovery and development of Thl7 cell-associated autoimmune diseases.
There is accordingly a need for compounds that inhibit RORc for use in treatment of autoimmune diseases such as rheumatoid arthritis, irritable bowel disease, psoriasis, psoriatic arthritis and spondyloarthriitis.
SUMMARY OF THE INVENTION
The invention p
Figure imgf000002_0001
wherein:
A is a group selected from:
Figure imgf000003_0001
Figure imgf000004_0001
p is from 0 to 3;
s is from 0 to 3 ;
R is: hydrogen; or Ci-6alkyl which may be unsubstituted or substituted one or more times with halo; and
each Re is independently: hydrogen; Ci-6alkyl; halo; Ci-6alkoxy; or cyano; wherein the Ci_6alkyl moieties may be unsubstituted or substituted one or more times with halo.
The compound may be selected from:
methyl 4-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]tetrahydropyran-4-carboxylate;
methyl 4-[2,5-difluoro-4-[[(3S,6S)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]tetrahydropyran-4-carboxylate;
(3S,6R)-2-[[2-fluoro-4-[4-(oxetan-3-ylmethoxymethyl)tetrahydropyran-4-yl]phenyl]methyl]-3- methyl-6-phenyl-thiazinane 1 , 1 -dioxide;
(2S)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-(oxetan-3-yl)propanamide;
(2R)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-(oxetan-3-yl)propanamide;
(2R)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-tetrahydropyran-4-yloxy-acetamide; (2S)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-tetrahydropyran-4-yloxy-acetamide;
(2R)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-(oxetan-3-yloxy)acetamide;
(2S)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-(oxetan-3-yloxy)acetamide;
(2S)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-hydroxy-2-methyl-propanamide;
(2R)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-hydroxy-2-methyl-propanamide;
2- [[6- [2,5-difluoro-4- [[(3 S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-oxaspiro[3.3]heptan-6-yl]oxy]acetamide;
2- [[6- [2,5-difluoro-4- [[(3 S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-oxaspiro[3.3]heptan-6-yl]oxy]-N-methyl-acetamide;
(3S,6R)-2-[[4-(6-allyloxy-2-oxaspiro[3.3]heptan-6-yl)-2,5-difluoro-phenyl]methyl]-3- methyl-6-phenyl-thiazinane 1 , 1 -dioxide;
3- [2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]cyclobut-2-en-l-one;
(2S)-4-cyano-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]butanamide;
(2R)-4-cyano-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]butanamide;
(2R)-2-(cyclopropylmethoxy)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl- thiazinan-2-yl]methyl]phenyl]acetamide;
(2S)-2-(cyclopropylmethoxy)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl- thiazinan-2-yl]methyl]phenyl]acetamide;
2- [[ 1 - [2,5-difluoro-4- [[(3 S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl] methyl]phenyl] - 1 -methyl-ethyl] amino] acetamide;
2- [[ 1 - [2,5-difluoro-4- [[(3 S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3,3-difluoro-cyclobutyl]amino]acetamide; 3-[[(lR)-l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]amino]cyclohex-2-en-l-one;
3- [[(lS)-l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]amino]cyclohex-2-en-l-one;
4-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]- 1 -methyl-2-oxabicyclo [2.1.1 ]hexan-3-one;
N Γ- [ 1 - [2,5 -difluoro-4- [ [(3S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-Nl-methyl-2-nitro-ethene-l,l-diamine;
2-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethylamino]acetamide;
N-cyclopropyl-4-[3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]tetrahydropyran-4-carboxamide;
N-(cyclopropylmethyl)-4-[3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan- 2-yl]methyl]phenyl]tetrahydropyran-4-carboxamide;
4-[3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]-N- (3-methoxycyclobutyl)tetrahydropyran-4-carboxamide;
4- [3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]-N- [(2R)-2-hydroxypropyl]tetrahydropyran-4-carboxamide;
4-[3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]-N- (3-hydroxycyclobutyl)tetrahydropyran-4-carboxamide;
4-[3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]-N- [l-(hydroxymethyl)cyclopropyl]tetrahydropyran-4-carboxamide;
N-( 1 -cyanocyclopropyl)-4- [3 -fluoro-4- [ [(3S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan- 2-yl]methyl]phenyl]tetrahydropyran-4-carboxamide;
4-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]- N-(3-hydroxycyclobutyl)tetrahydropyran-4-carboxamide;
4-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]- N-(3-hydroxycyclobutyl)tetrahydropyran-4-carboxamide;
(3S,6R)-2-[[2,5-difluoro-4-[(3S,4R)-3-fluoro-4-(l,2,4-triazol-4-yl)-l- piperidyl]phenyl]methyl] -3-methyl-6-phenyl-thiazinane 1 , 1 -dioxide; (3S,6R)-2-[[2,5-difluoro-4-[(3R,4S)-3-fluoro-4-(l ,2,4-triazol-4-yl)-l- piperidyl]phenyl]methyl] -3-methyl-6-phenyl-thiazinane 1 , 1 -dioxide;
N-cyclopropyl-2-[4-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]tetrahydropyran-4-yl]oxy-acetamide;
2- [[ 1 - [2,5-difluoro-4- [[(3 S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl] methyl]phenyl] - 1 -methyl-ethyl] amino] acetamide;
(lR,5S)-l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l ,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-oxabicyclo[3.1.0]hexan-2-one;
3-(cyanomethyl)-l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]cyclobutanecarboxamide;
3-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l ,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethylamino]-3-(methylamino)prop-2-enenitrile;formic acid;
N-[3-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]oxetan-3-yl]cyclopropanecarboxamide;
(lR,5S)-l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l ,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-oxabicyclo[3.1.0]hexan-2-one; and
2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]- 2-phenyl -ethanol .
The invention also provides and pharmaceutical compositions comprising the compounds, methods of using the compounds, and methods of preparing the compounds.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an," and "the" include plural referents unless the context clearly dictates otherwise. In some instances dashes ("-") may be used interchangeably within definitions (for example, "alkoxyalkyl" omits the dash found in the equivalent term "alkoxy- alkyl").
"Alkyl" means the monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. "Lower alkyl" refers to an alkyl group of one to six carbon atoms, i.e. Ci-C6alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec -butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
"Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g. , ethenyl, propenyl, and the like.
"Alkynyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g. , ethynyl, propynyl, and the like.
"Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.
"Alkoxy" and "alkyloxy", which may be used interchangeably, mean a moiety of the formula -OR, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
"Alkoxyalkyl" means a moiety of the formula Ra-0-Rb-, where Ra is alkyl and Rb is alkylene as defined herein. Exemplary alkoxyalkyl groups include, by way of example, 2-methoxy ethyl, 3-methoxypropyl, 1 -methyl -2 -methoxyethyl, l-(2-methoxyethyl)-3-methoxypropyl, and l-(2- methoxyethyl)-3 -methoxypropyl.
"Alkoxyalkoxy' means a group of the formula -O-R-R' wherein R is alkylene and R' is alkoxy as defined herein.
"Alkylcarbonyl" means a moiety of the formula -C(0)-R, wherein R is alkyl as defined herein.
"Alkoxycarbonyl" means a group of the formula -C(0)-R wherein R is alkoxy as defined herein.
"Alkylcarbonylamino" means a group of the formula -R-C(0)-NR'- wherein R is alkyl and R' is hydrogen or alkyl.
"Alkylcarbonylalkyl" means a group of the formula -R-C(0)-R' wherein R is alkylene and R' is alkyl as defined herein.
"Alkoxyalkylcarbonyl" means a moiety of the formula -C(0)-R-R' , wherein R is alkylene and R' is alkoxy as defined herein.
"Alkoxycarbonylalkyl" means a group of the formula -R-C(0)-R wherein R is alkylene and R' is alkoxy as defined herein.
"Alkoxycarbonylamino" means a moiety of the formula R-C(0)-NR'-, wherein R is alkoxy and R' is hydrogen or alkyl as defined herein. "Alkoxycarbonylaminoalkyl" means a moiety of the formula R-C(0)-NR'-R"-, wherein R is alkoxy, R' is hydrogen or alkyl, and R" is alkylene as defined herein.
"Alkoxycarbonylalkoxy"means a group of the formula -0-R-C(0)-R' wherein R is alkylene and R' is alkoxy as defined herein.
"Hydroxycarbonylalkoxy" means a group of the formula -0-R-C(0)-OH wherein R is alkylene as defined herein.
"Alkylaminocarbonylalkoxy" means a group of the formula -0-R-C(0)-NHR' wherein R is alkylene and R' is alkyl as defined herein.
"Dialkylaminocarbonylalkoxy" means a group of the formula -0-R-C(0)-NR'R" wherein R is alkylene and R' and R" are alkyl as defined herein.
"Alkylaminoalkoxy" means a group of the formula -O-R-NHR' wherein R is alkylene and R' is alkyl as defined herein.
"Dialkylaminoalkoxy" means a group of the formula -O-R-NR'R' wherein R is alkylene and R' and R" are alkyl as defined herein.
"Alkylsulfonyl" means a moiety of the formula - S02-R, wherein R is alkyl as defined herein.
"Alkylsulfonylalkyl means a moiety of the formula -R'-S02-R" where where R' is alkylene and R" is alkyl as defined herein.
"Alkylsulfonylalkoxy" means a group of the formula -0-R-S02-R' wherein R is alkylene and R' is alkyl as defined herein.
"Amino means a moiety of the formula -NRR' wherein R and R' each independently is hyrdogen or alkyl as defined herein. "Amino thus includes "alkylamino (where one of R and R' is alkyl and the other is hydrogen) and "dialkylamino (where R and R' are both alkyl.
"Aminocarbonyl" means a group of the formula -C(0)-R wherein R is amino as defined herein. "N-hydroxy-aminocarbonyl" means a group of the formula -C(0)-NR-OH wherein R is hydrogen or alkyl as defined herein.
"N-alkoxy-aminocarbonyl" means a group of the formula -C(0)-NR-R' wherein R is hydrogen or alkyl and R' is alkoxy as defined herein.
"Aminocarbonylaminoalkyl" means a group of the formula R2N-C(0)-NR'-R"- wherein each R is independently hydrogen or alkyl, R' is hydrogen or alkyl, and R" is alkylene as defined herein.
"N-alkyl-aminocarbonyl means a group of the formula -C(0)-NH-R wherein R is alkyl as defined herein.
"N-hydroxy-N-alkylaminocarbonyl means a group of the formula -C(0)-NRR' wherein R is alkyl as defined herein and R' is hydroxy. "N-alkoxy-N-alkylaminocarbonyl" means a group of the formula -C(0)-NRR' wherein R is alkyl and R' is alkoxy as defined herein.
"N^-di-C!^alkyl-aminocarbonyl" means a group of the formula -C(0)-NRR' wherein R and R' are alkyl as defined herein.
"Aminosulfonyl" means a group of the formula -S02-NH2.
"N-alkylaminosulfonyl" means a group of the formula -S02-NHR wherein R is alkyl as defined herein.
"Ν,Ν-dialkylaminosulfonyl" means a group of the formula -S02-NRR' wherein R and R' are alkyl as defined herein.
"Alkylsulfonylamino" means a group of the formula -NR'-S02-R wherein R id alkyl and R' is hydrogen or alkyl as defined herein.
"N-(alkylsulfonyl)-aminoalkyl" means a group of the formula -R-NH-S02-R' wherein R is alkylene and R' is alkyl as defined herein.
"N-(Alkylsulfonyl)aminocarbonyl" means a group of the formula -C(0)-NH-S02-R wherein wherein R is alkyl as defined herein.
"N-(Alkylsulfonyl)-N-alkylaminocarbonyl" means a group of the formula -C(0)-NR-S02-R' wherein wherein R and R' are alkyl as defined herein.
"N-Alkoxyalkyl-aminocarbonyl" means a group of the formula -C(0)-NR-R'-OR" wherein R is hydrogen or alkyl, R' is alkylene, and R" is alkyl as defined herein.
"N-Hydroxyalkyl-aminocarbonyl" means a group of the formula -C(0)-NR-R'-OH" wherein R is hydrogen or alkyl and R' is alkylene as defined herein.
"Alkoxyamino" means a moiety of the formula -NR-OR' wherein R is hydrogen or alkyl and R' is alkyl as defined herein.
"Alkylsulfanyl" means a moiety of the formula -SR wherein R is alkyl as defined herein.
"Aminoalkyl" means a group -R-R' wherein R' is amino and R is alkylene as defined herein.
"Aminoalkyl" includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of "aminoalkyl" may be substituted once or twice with alkyl to provide
"alkylaminoalkyl" and "dialkylaminoalkyl" respectively. "Alkylaminoalkyl" includes
methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl and the like.
"Dialkylaminoalkyl" includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N- methyl-N-ethylaminoethyl, and the like.
"Aminoalkoxy" means a group -OR-R' wherein R' is amino and R is alkylene as defined herein.
"Alkylsulfonylamido" means a moiety of the formula -NR'S02-R wherein R is alkyl and R' is hydrogen or alkyl. "Aminocarbonyloxyalkyl" or "carbamylalkyl" means a group of the formula -R-0-C(0)-NR'R" wherein R is alkylene and R', R" each independently is hydrogen or alkyl as defined herein.
"Alkynylalkoxy" means a group of the formula -O-R-R' wherein R is alkylene and R' is alkynyl as defined herein.
"Aryl" means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring. The aryl group can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, of which may be optionally substituted as defined herein.
"Arylalkyl" and "Aralkyl", which may be used interchangeably, mean a radical-RaRb where Ra is an alkylene group and Rb is an aryl group as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like are examples of arylalkyl.
"Arylsulfonyl means a group of the formula -S02-R wherein R is aryl as defined herein.
"Aryloxy" means a group of the formula -O-R wherein R is aryl as defined herein.
"Aralkyloxy" means a group of the formula -O-R-R" wherein R is alkylene and R' is aryl as defined herein.
"Carboxy" or "hydroxycarbonyl", which may be used interchangeably, means a group of the formula -C(0)-OH.
"Cyanoalkyl" " means a moiety of the formula -R'-R", where R' is alkylene as defined herein and R" is cyano or nitrile.
"Cycloalkyl" means a monovalent saturated carbocyclic moiety consisting of mono- or bicyclic rings. Particular cycloalkyl are unsubstituted or substituted with alkyl. Cycloalkyl can optionally be substituted as defined herein. Unless defined otherwise, cycloalkyl may be optionally substitued with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated (cycloalkenyl) derivatives thereof.
"Cycloalkenyl" means a cycloalkyl as defined herein that includes at least one double bond or unsaturation. Exemplary cycloalkenyl include cyclohexenyl, cyclopentenyl, cyclobutenyl and the like.
"Cycloalkylalkyl" means a moiety of the formula -R'-R", where R' is alkylene and R" is cycloalkyl as defined herein. "Cycloalkylalkoxy" means a group of the formula -O-R-R' wherein R is alkylene and R' is cycloalkyl as defined herein.
"Cycloalkylcarbonyl" means a moiety of the formula -C(0)-R, wherein R is cycloalkyl as defined herein.
"Cs^cycloalkyl-C!^alkyl-carbonyl" means a moiety of the formula -C(0)-R, wherein R is cycloalkylalkyl as defined herein.
"Cyanoalkylcarbonyl" means a moiety of the formula -C(0)-R-R' , wherein R is alkylene as defined herein and R' is cyano or nitrile.
"N-Cyano-aminocarbonyl" means a moiety of the formula -C(0)-NHR, wherein R is cyano or nitrile.
"N-Cyano-N-alkyl-aminocarbonyl" means a moiety of the formula -C(0)-NRR' -R, wherein R' is alkyl as defined herein and R is cyano or nitrile.
"Cycloalkylsulfonyl" means a group of the formula -S02-R wherein R is cycloalkyl as defined herein.
"Cycloalkylalkylsulfonyl" means a group of the formula -S02-R wherein R is cycloalkylalkyl as defined herein.
"Formyl" means a moiety of the formula -C(0)-H.
"Heteroaryl" means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like, each of which may be optionally substituted as defined herein.
Heteroarylalkyl" or "heteroaralkyl" means a group of the formula -R-R' wherein R is alkylene and R' is heteroaryl as defined herein.
"Heteroarylsulfonyl means a group of the formula -S02-R wherein R is heteroaryl as defined herein.
"Heteroaryloxy" means a group of the formula -O-R wherein R is heteroaryl as defined herein. "Heteroaralkyloxy" means a group of the formula -O-R-R" wherein R is alkylene and R' is heteroaryl as defined herein.
The terms "halo", "halogen" and "halide", which may be used interchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.
"Haloalkyl" means alkyl as defined herein in which one or more hydrogen has been replaced with same or different halogen. Exemplary haloalkyls include -CH2C1,
-CH2CF3, -CH2CC13, perfluoroalkyl (e.g., -CF3), and the like.
"Haloalkoxy" means a moiety of the formula -OR, wherein R is a haloalkyl moiety as defined herein. An exemplary haloalkoxy is difluoromethoxy.
"Heterocycloamino" means a saturated ring wherein at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.
"Heterocyclyl" means a monovalent saturated moiety, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, azepinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl and the like. Such heterocyclyl may be optionally substituted as defined herein.
"Heterocyclylalkyl" means a moiety of the formula -R-R' wherein R is alkylene and R' is heterocyclyl as defined herein.
"Heterocyclyloxy" means a moiety of the formula -OR wherein R is heterocyclyl as defined herein.
"Heterocyclylalkoxy" means a moiety of the formula -OR-R' wherein R is alkylene and R' is heterocyclyl as defined herein.
"Hydroxyalkoxy" means a moiety of the formula -OR wherein R is hydroxyalkyl as defined herein.
"Hydroxyalkylamino" means a moiety of the formula -NR-R' wherein R is hydrogen or alkyl and R' is hydroxyalkyl as defined herein.
"Hydroxyalkylaminoalkyl" means a moiety of the formula -R-NR'-R" wherein R is alkylene, R' is hydrogen or alkyl, and R" is hydroxyalkyl as defined herein.
"Hydroxycarbonylalkyl" or "carboxyalkyl" means a group of the formula -R-(CO)-OH where R is alkylene as defined herein.
"Hydroxycarbonylalkoxy" means a group of the formula -0-R-C(0)-OH wherein R is alkylene as defined herein. "Hydroxyalkylcarbonyl" means a moiety of the formula -C(0)-R-R' , wherein R is alkylene as defined herein and R' is hydroxy.
"Hydroxyalkyloxycarbonylalkyl" or "hydroxyalkoxycarbonylalkyl" means a group of the formula -R-C(0)-0-R-OH wherein each R is alkylene and may be the same or different.
"Hydroxyalkyl" means an alkyl moiety as defined herein, substituted with one or more, for example, one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group. Representative examples include, but are not limited to, hydroxymethyl,
2- hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl,
3- hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-l-hydroxymethylethyl,
2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl
"Hydroxycycloalkyl" means a cycloalkyl moiety as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been replaced with a hydroxy substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.
"Oxo" means a group of the formula =0 (i.e., an oxygen with a double bond). Thus, for example, a 1-oxo-ethyl group is an acetyl group.
"Alkoxy hydroxyalkyl" and "hydroxy alkoxyalkyl", which may be used interchangeably, means an alkyl as defined herein that is substituted at least once with hydroxy and at least once with alkoxy.
"Alkoxy hydroxyalkyl" and "hydroxy alkoxyalkyl" thus encompass, for example, 2-hydroxy-3- methoxy-propan-l-yl and the like.
"Urea'Or "ureido" means a group of the formula -NR'-C(0)-NR"R"' wherein R', R" and R'" each independently is hydrogen or alkyl.
"Carbamate" means a group of the formula -0-C(0)-NR'R" wherein R' and R" each
independently is hydrogen or alkyl.
"Carboxy" means a group of the formula -0-C(0)-OH.
"Sulfonamido" means a group of the formula -S02-NR'R" wherein R', R" and R'" each independently is hydrogen or alkyl.
"Optionally substituted" when used in association with an "aryl", phenyl", "heteroaryl"
"cycloalkyl" or "heterocyclyl" moiety means that such moiety may be unsubstituted (i.e., all open valencies are occupied by a hydrogen atom) or substituted with specific groups as related herein.
"Leaving group" means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions. Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like. "Modulator" means a molecule that interacts with a target. The interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein.
"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
"Disease" and "Disease state" means any disease, condition, symptom, disorder or indication.
"Inert organic solvent" or "inert solvent" means the solvent is inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, Ν,Ν-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, ferf-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.
"Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
"Pharmaceutically acceptable salts" of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound.
It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.
"Protective group" or "protecting group" means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon the protective groups to block reactive nitrogen and/or oxygen atoms present in the reactants. For example, the terms "amino-protecting group" and "nitrogen protecting group" are used interchangeably herein and refer to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures. Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl
(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, ferf-butoxycarbonyl (BOC), and the like. The artisan in the art will know how to chose a group for the ease of removal and for the ability to withstand the following reactions.
"Solvates" means solvent additions forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H20, such combination being able to form one or more hydrate.
"Arthritis" means a disease or condition that causes damage to joints of the body and pain associated with such joint damage. Arthritis includes rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, and other arthritic conditions.
"Respiratory disorder" refers to, without limitation, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and the like.
"Subject" means mammals and non-mammals. Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "subject" does not denote a particular age or sex.
"Therapeutically effective amount" means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The "therapeutically effective amount" will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.
The terms "those defined above" and "those defined herein" when referring to a variable incorporates by reference the broad definition of the variable as well as particular definitions, if any.
"Treating" or "treatment" of a disease state includes, inter alia, inhibiting the disease state, i.e. , arresting the development of the disease state or its clinical symptoms, and/or relieving the disease state , i. e. , causing temporary or permanent regression of the disease state or its clinical symptoms.
The terms "treating", "contacting" and "reacting" when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
Nomenclature and Structures
In general, the nomenclature and chemical names used in this Application are based on
ChembioOffice™ by CambridgeSoft™. Any open valency appearing on a carbon, oxygen sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen atom unless indicated otherwise. Where a nitrogen-containing heteroaryl ring is shown with an open valency on a nitrogen atom, and variables such as Ra, Rb or Rc are shown on the heteroaryl ring, such variables may be bound or joined to the open valency nitrogen. Where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral center are encompassed by the structure. Where a structure shown herein may exist in multiple tautomeric forms, all such tautomers are encompassed by the structure. The atoms represented in the structures herein are intended to encompass all naturally occurring isotopes of such atoms. Thus, for example, the hydrogen atoms represented herein are meant to include deuterium and tritium, and the carbon atoms are meant to include C13 and C14 isotopes. One or more carbon atom(s) of a compound of the invention may be replaced by a silicon atom(s), and it is contemplated that one or more oxygen atom(s) of a compound of the invention may be replaced by a sulfur or selenium atom(s).
Compounds of the Invention
In a first aspect, the i
Figure imgf000017_0001
wherein:
A is a group selected from:
Figure imgf000018_0001

Figure imgf000019_0001
p is from 0 to 3;
s is from 0 to 3 ;
R is: hydrogen; or Ci-6alkyl which may be unsubstituted or substituted one or more times with halo; and
each Re is independently: hydrogen; Ci_6alkyl; halo; Ci_6alkoxy; or cyano; wherein the Ci-6alkyl moieties may be unsubstituted or substituted one or more times with halo.
In certain embodiments of formula I the compound is selected from:
methyl 4-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]tetrahydropyran-4-carboxylate;
methyl 4-[2,5-difluoro-4-[[(3S,6S)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]tetrahydropyran-4-carboxylate;
(3S,6R)-2-[[2-fluoro-4-[4-(oxetan-3-ylmethoxymethyl)tetrahydropyran-4-yl]phenyl]methyl]-3- methyl-6-phenyl-thiazinane 1 , 1 -dioxide;
(2S)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-(oxetan-3-yl)propanamide;
(2R)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-(oxetan-3-yl)propanamide;
(2R)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-tetrahydropyran-4-yloxy-acetamide; (2S)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-tetrahydropyran-4-yloxy-acetamide;
(2R)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-(oxetan-3-yloxy)acetamide;
(2S)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-(oxetan-3-yloxy)acetamide;
(2S)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-hydroxy-2-methyl-propanamide;
(2R)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-hydroxy-2-methyl-propanamide;
2- [[6- [2,5-difluoro-4- [[(3 S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-oxaspiro[3.3]heptan-6-yl]oxy]acetamide;
2- [[6- [2,5-difluoro-4- [[(3 S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-oxaspiro[3.3]heptan-6-yl]oxy]-N-methyl-acetamide;
(3S,6R)-2-[[4-(6-allyloxy-2-oxaspiro[3.3]heptan-6-yl)-2,5-difluoro-phenyl]methyl]-3- methyl-6-phenyl-thiazinane 1 , 1 -dioxide;
3- [2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]cyclobut-2-en-l-one;
(2S)-4-cyano-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]butanamide;
(2R)-4-cyano-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]butanamide;
(2R)-2-(cyclopropylmethoxy)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl- thiazinan-2-yl]methyl]phenyl]acetamide;
(2S)-2-(cyclopropylmethoxy)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl- thiazinan-2-yl]methyl]phenyl]acetamide;
2- [[ 1 - [2,5-difluoro-4- [[(3 S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl] methyl]phenyl] - 1 -methyl-ethyl] amino] acetamide;
2- [[ 1 - [2,5-difluoro-4- [[(3 S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3,3-difluoro-cyclobutyl]amino]acetamide; 3-[[(lR)-l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]amino]cyclohex-2-en-l-one;
3- [[(lS)-l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]amino]cyclohex-2-en-l-one;
4-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]- 1 -methyl-2-oxabicyclo[2.1.1 ]hexan-3-one;
N Γ - [ 1 - [2,5 -difluoro-4- [ [(3S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-Nl-methyl-2-nitro-ethene-l,l -diamine;
2-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethylamino]acetamide;
N-cyclopropyl-4-[3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]tetrahydropyran-4-carboxamide;
N-(cyclopropylmethyl)-4-[3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan- 2-yl]methyl]phenyl]tetrahydropyran-4-carboxamide;
4-[3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]-N- (3-methoxycyclobutyl)tetrahydropyran-4-carboxamide;
4- [3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]-N- [(2R)-2-hydroxypropyl]tetrahydropyran-4-carboxamide;
4-[3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]-N- (3-hydroxycyclobutyl)tetrahydropyran-4-carboxamide;
4-[3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]-N- [l-(hydroxymethyl)cyclopropyl]tetrahydropyran-4-carboxamide;
N-( 1 -cyanocyclopropyl)-4- [3 -fluoro-4- [ [(3S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan- 2-yl]methyl]phenyl]tetrahydropyran-4-carboxamide;
4-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]- N-(3-hydroxycyclobutyl)tetrahydropyran-4-carboxamide;
4-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]- N-(3-hydroxycyclobutyl)tetrahydropyran-4-carboxamide;
(3S,6R)-2-[[2,5-difluoro-4-[(3S,4R)-3-fluoro-4-(l,2,4-triazol-4-yl)-l- piperidyl]phenyl]methyl] -3-methyl-6-phenyl-thiazinane 1 , 1 -dioxide; (3S,6R)-2-[[2,5-difluoro-4-[(3R,4S)-3-fluoro-4-(l,2,4-triazol-4-yl)-l- piperidyl]phenyl]methyl] -3-methyl-6-phenyl-thiazinane 1 , 1 -dioxide;
N-cyclopropyl-2-[4-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]tetrahydropyran-4-yl]oxy-acetamide;
2- [[ 1 - [2,5-difluoro-4- [[(3 S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl] methyl]phenyl] - 1 -methyl-ethyl] amino] acetamide;
(lR,5S)-l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-oxabicyclo[3.1.0]hexan-2-one;
3-(cyanomethyl)-l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl] methyl]phenyl ] cyclobutanecarboxamide ;
3-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethylamino]-3-(methylamino)prop-2-enenitrile;formic acid;
N-[3-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]oxetan-3-yl]cyclopropanecarboxamide;
(lR,5S)-l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-oxabicyclo[3.1.0]hexan-2-one; and
2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]- 2-phenyl -ethanol .
In certain embodiments of Formula I, p is 0.
In certain embodiments of Formula I, p is 1.
In certain embodiments of Formula I, p is 2.
In certain embodiments of Formula I, s is 0.
In certain embodiments of Formula I, s is 1.
In certain embodiments of Formula I, s is 2.
In certain embodiments of Formula I, each Re is independently: hydrogen; or halo.
In certain embodiments of Formula I, each Re is independently: hydrogen; or fluoro.
In certain embodiments of Formula I, Re is hydrogen.
In certain embodiments of Formula I, Re is Ci_6alkyl.
In certain embodiments of Formula I, Re is halo. In certain embodiments of Formula I, Re is Ci-6alkoxy.
In certain embodiments of Formula I, Re is cyano.
In certain embodiments of Formula I, Re is halo-Ci_6alkyl.
In another asp
Figure imgf000023_0001
or a pharmaceutically acceptable salt thereof,
wherein:
p is from 0 to 3;
q is from 0 to 3;
s is from 0 to 3;
Het is heteroaryl selected from: oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; pyrazolyl;triazolyl; oxadiazolyl; thiadiazolyl; pyridinyl; pyrimidinyl; pyrazinyl; or imidazolyl;
A is: -CH(CH3)-NRa-CH2-; -CH(CH3)-NRa-C(0)-; or -CH(CH3)-NRa-C(0)-CH2-;
R is: hydrogen; or Ci_6alkyl which may be unsubstituted or substituted one or more times with halo;
each R9 is independently: Ci_6alkyl; halo; Ci_6alkoxy; or cyano; wherein the Ci_6alkyl moieties may be unsubstituted or substituted one or more times with halo;
each R10 is independently: Ci-6alkyl; hydroxy; oxo; cyano; halo; hydroxy-Ci-6alkyl; or C i_6alkoxy-C i-6alkyl ;
Ra is: hydrogen; or Ci-6alkyl and
each Re is independently:
hydrogen;
Ci_6alkyl;
halo;
Ci_6alkoxy; or
cyano; wherein the Ci-6alkyl moieties may be unsubstituted or substituted one or more times with halo.
In certain embodiments of Formula II, the compound is selected from:
l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-tMazinan-2-yl]methyl]phenyl]- N-(isoxazol-4-ylmethyl)ethanamine;
l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]- N-(oxazol-4-ylmethyl)ethanamine;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]isoxazole-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-5-methyl-isoxazole-3-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-2-isoxazol-4-yl-acetamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-3-methyl-lH-pyrazole-4-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-3-methyl-lH-pyrazole-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]pyrazine-2-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-l-methyl-pyrazole-3-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-lH-imidazole-4-carboxarnide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-3-methyl-isoxazole-4-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-l-methyl-pyrazole-4-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-l-methyl-imidazole-4-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]pyrimidine-5-carboxarnide; N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-4-methyl-oxazole-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]oxazole-4-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]pyrimidine-4-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-3-methyl-isoxazole-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-lH-pyrazole-3-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-2-methyl-pyrazole-3-carboxamide;
3-amino-N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-lH-l,2,4-triazole-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]thiazole-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-5-methyl-l,3,4-oxadiazole-2-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-3-methoxy-isoxazole-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]oxazole-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]isoxazole-3-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]isoxazole-3-carboxamide;
2-amino-N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]thiazole-4-carboxamide; and
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]thiadiazole-4-carboxamide.
In certain embodiments of Formula II, p is from 0 to 2. In certain embodiments of Formula ] I. P is O or 1
In certain embodiments of Formula ] I. P is 0.
In certain embodiments of Formula ] I. P is 1.
In certain embodiments of Formula ] I. P is 2.
In certain embodiments of Formula ] I. P is 3.
In certain embodiments of Formula ] i. q is 0.
In certain embodiments of Formula ] i. q is 1.
In certain embodiments of Formula ] i. q is 2.
In certain embodiments of Formula ] i. q is O or 1
In certain embodiments of Formula ] I, s is 0.
In certain embodiments of Formula ] I, s is 1.
In certain embodiments of Formula ] I, s is 2.
In certain embodiments of Formula ] I, s is O or 1
In certain embodiments of Formula ]
In certain embodiments of Formula II, A is -CH(CH3)-NRa-CH2-
In certain embodiments of Formula II, A is -CH(CH3)-NRa-C(0)-;
In certain embodiments of Formula II, A is -CH(CH3)-NRa-C(0)-CH2-; In certain embodiments of formula I, Het is: oxadiazolyl; or thiadiazolyl
In certain embodiments of formula I, Het is imidazolyl.
In certain embodiments of formula I, Het is pyrazolyl.
In certain embodiments of formula I, Het is isoxazolyl.
In certain embodiments of formula I, Het is oxazolyl.
In certain embodiments of formula I, Het is thiazolyl.
In certain embodiments of formula I, Het is oxadiazolyl.
In certain embodiments of formula I, Het is triazolyl.
In certain embodiments of formula I, Het is tetrazolyl.
In certain embodiments of formula I, Het is thiophenyl.
In certain embodiments of formula I, Het is furanyl.
In certain embodiments of formula I, Het is pyridinyl.
In certain embodiments of formula I, Het is pyrimidinyl
In certain embodiments of formula I, Het is pyridazinyl In certain embodiments of
In certain embodiments of
In certain embodiments of
In certain embodiments of R is hydrogen.
In certain embodiments of R3 is Ci_6alkyl.
In certain embodiments of each R9 is independently: Ci-6alkyl; halo; or halo-Ci_6alkyl
In certain embodiments of Formula R is Ci_6alkyl.
In certain embodiments of Formula R9 is halo.
In certain embodiments of Formula R9 is Ci_6alkoxy.
In certain embodiments of Formula R9 is cyano.
In certain embodiments of Formula R9 is halo-Ci_6alkyl.
In certain embodiments of Formula each R9 is independently: fluoro; chloro; or trifluoromethyl.
In certain embodiments of Formula I R is: Ci_6alkyl; hydroxy; oxo; or hydroxy-C i _6alkyl .
of Formula II , R10 is hydroxy.
of Formula II , R10 is oxo.
of Formula II , R10 is cyano.
of Formula II , R10 is halo.
of Formula II , R10 is hydroxy-Ci_6alkyl.
of Formula II , R10 is Ci-6alkoxy-Ci_6alkyl.
In certain embodiments of Formula II, each Re is independently:
hydrogen; Ci-6alkyl; halo; or cyano; wherein the Ci-6alkyl moieties may be unsubstituted or substituted one or more times with halo;
In certain embodiments of Formula II, each Re is independently: hydrogen; Ci_ 6alkyl; halo; or halo-Ci_6alkyl.
In certain embodiments of Formula II, each Re is independently: hydrogen; Ci_
6alkyl; or halo.
In certain embodiments of Formula II, each Re is independently: hydrogen; or halo. In certain embodiments of Formula II, each Re is independently: hydrogen; or fluoro.
In certain embodiments of Formula Π, Re is hydrogen.
In certain embodiments of Formula II, Re is Ci_6alkyl.
In certain embodiments of Formula II, Re is halo.
In certain embodiments of Formula II, Re is Ci-6alkoxy.
In certain embodiments of Formula II, Re is cyano.
In certain embodiments of Formula II, Re is halo-Ci_6alkyl.
In certain embodiments of Formula II, Rf is: Ci-6alkyl; halo; oxo; hydroxy; acetyl; or Ci_6alkoxy.
Methods
The invention also provides a method for treating a disease or condition mediated by or otherwise associated with the RORc receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention.
The disease may be arthritis such as rheumatoid arthritis or osteoarthritis.
The disease may be asthma or COPD.
The disease may be psoriasis.
The disease may be muscular distrophy.
Representative compounds in accordance with the methods of the invention are shown in the experimental examples below.
Synthesis
Compounds of the present invention can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below.
The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagentsor Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions , Wiley & Sons: New York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application. The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein may be conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about -78 °C to about 150 °C, for example, from about 0 °C to about 125 °C, or conveniently at about room (or ambient) temperature, e.g., about 20 °C.
Scheme A below illustrates one synthetic procedure usable to prepare specific compounds of formula I, wherein LG is a leaving group such as halo, sulfonate, or the like, and m, n, p, q, X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Rb and Rc are as defined herein.
Figure imgf000030_0001
SCHEME A
In step 1 of Scheme A, alkyl amine a is reacted with benzyl sulfonyl chloride b to form sulfonamide compound c. The reaction of step 1 may be carried out in a polar aprotic solvent such as THF or methylene chloride, and in the presence of a tertiary amine base or weak base such as potassium carbonate. The leaving group of compound a may be bromo in certain embodiments. Similarly, the chloro group of compound b may in certain embodiments be replaced by other halo or leaving group.
A cyclization reaction is carried out in step 2 to afford thiazinane compound d. The cyclization may be achieved in the presence of a strong base such as an alkyl lithium reagent, using polar aprotic solvent under anhydrous conditions.
In step 3, thiazinane compound c is reacted with aryalkyl halide compound e to yield aralkyl thiazinane f. The reaction of step 3 may be carried out in the presence of a strong base such as sodium hydride under anhydrous polar aprotic solvent conditions. The bromo groups of compound e may be replaced by other suitable leaving groups used in the art.
Thiazinane compound f may then be reacted with oxoethyl zinc halide reagent g in step 4 to provide ester compound h. This reaction may be carried out in the presence of suitable palladium catalyst under polar aprotic conditions in a solvent such as dry
tetrahydrofuran.
In step 5, ester compound h is reacted with hydrazine to yield the corresponding hydrazide compound i.
In step 6, hydrazide compound is reacted with acyl halide reagent } to afford an acyl hydrazide compound k.
In step 7 a cyclization is carried out to form an oxadiazole group, resulting in the compound 1, whihch is a compound of formula I in accordance with the invention.
Many variations in the above procedure are possible and will suggest themselves to those skilled in the art. For example, reagent g may be replaced by the corresponding thionoester to provide a thiadiazole group in the final compound. The group Ra may be replaced by an alkyl group, or may omitted from reagent g and introduced (if desired) in a later step. Similarly, the group R10 may omitted from acyl reagent} and, if desired, introduced in a later step.
Scheme B below shows another synthetic procedure usable to prepare specific compounds of formula I, wherein TBS is tri-(tert-butyl)-silyl, and m, n, p, q, X\ X , X", X , Y, R1, R2, R3, R4, R5, R6, R9 and R10 are as defined herein.
Figure imgf000032_0001
SCHEME B
In step 1 of Scheme B, tri-(tert-butyl)-slilyloxy amine m is reacted with benzyl sulfonyl chloride b, as described above with reference to Scheme A, to form sulfonamide compound n. In certain embodiments the tri-(tert-butyl)-slilyloxy group may be replaced with other leaving groups. In step 2, sulfonamide compound n is reacted with iodochloromethane to provide an alkenylsulfonamide compound o. This reaction may be achieved in the presence of a strong base such as an alkyl lithium reagent, using polar aprotic solvent such as THF under anhydrous conditions. In certain embodiments iodochloromethane may be replaced with other methylene reagents.
In step 3, a cyclization reaction is affected to provide oxathiazepane compound p_. The cyclization may be carried out in the presence of an amine base under polar aprotic solvent conditions.
In step 4, oxathiazepane compound p_ is reacted with aryalkyl halide compound e to yield aralkyl oxathiazepane compound q, in the manner described above with reference to Scheme A.
Steps 5-8 may then be carried out in the manner described above for steps 4-7 of Scheme A. Briefly, oxathiazepane compound q is reacted with zinc halide reagent g in step 5 to provide ester compound r, which is then reacted with hydrazine in step 6 to give the
corresponding hydrazide compound s. Hydrazide compound s may then b acylated in step 7 to make compound t, followed by ring closure in step 8, to afford sultam compound u, which is a compound of formula I in accordance with the invention.
Many variations on the procedure Scheme B are possible and will suggest themselves to those skilled in the art. Specific details for producing compounds of the invention are described in the Examples below.
Administration and Pharmaceutical Composition
The invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a
pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.
In general, the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, for example 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.
Compounds of the invention may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous)
administration or in a form suitable for administration by inhalation or insufflation. A particular manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
A compound or compounds of the invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use.
Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
The compounds of the invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets may contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.
Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The compounds of the invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
The compounds of the invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. The compounds of the invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
The compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
The subject compounds may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example,
dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatine or blister packs from which the powder may be administered by means of an inhaler.
When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support. The compound of interest can also be combined with a penetration enhancer, e.g., Azone (l-dodecylazacycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.
The pharmaceutical preparations may be in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Representative pharmaceutical formulations containing a compound of the present invention are described below.
Utility
The compounds of the invention are useful for treatment of immune disorders generally. The compounds may be used for treatment of arthritis, including rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, and other arthritic conditions.
The compounds may be used for treatment of respiratory disorders such as chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and the like.
The compounds may be used for treatment of gastrointestinal disorder ("GI disorder") such as
Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with GI distension, and the like.
The compounds may be used for treatment of psoriasis, muscular sclerosis, Sjogren' s disease, lupus, and pulmonary fibrosis.
GENERAL EXPERIMENTAL LCMS methods:
High Pressure Liquid Chromatography - Mass Spectrometry (LCMS) experiments to determine retention times and associated mass ions were performed using one of the following methods:
Method A: Compounds were analysed using the following conditions: Experiments were performed on a Waters ZMD single quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC system with UV diode array detector and 100 position autosampler. The spectrometer has an electrospray source operating in positive and negative ion mode. This system uses a Phenomenex Luna 3 μπι CI 8(2) 30 x 4.6 mm column at ambient temperature and a 2.0 mL / minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 min followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 min. This was maintained for 1 min before returning to 95% solvent A and 5% solvent B over the next 0.5 min. Total run time was 6 min.
Method B: Compounds were analysed using the following conditions: Experiments were performed on a Waters Micromass ZQ2000 quadrupole mass spectrometer linked to a Waters Acquity UPLC system with a PDA UV detector. The spectrometer has an electrospray source operating in positive and negative ion mode. This system uses an Acquity BEH CI 8 1.7 μπι 100 x 2.1 mm column, maintained at 40 °C or an Acquity BEH Shield RP18 1.7 μπι 100 x 2.1 mm column, maintained at 40 °C and a 0.4 mL / minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.4 min followed by a gradient up to 5% solvent A and 95% solvent B over the next 5.6 min. This was maintained for 0.8 min before returning to 95% solvent A and 5% solvent B over the next 1.2 min. Total run time was 8 min.
NMR methods:
1H NMR spectra were recorded at ambient temperature or at 80 °C where indicated using one of the following machines: Varian Unity Inova (400 MHz) spectrometer with a triple resonance 5mm probe, Bruker Avance DRX 400 (400 MHz) spectrometer with a triple resonance 5mm probe, a Bruker Avance DPX 300 (300 MHz) equipped with a standard 5 mm dual frequency probe for detection of 1H and 13C, Bruker Fourier 300MHz system equipped with a standard 5 mm
Figure imgf000038_0001
probe, a Bruker AVIII (400 MHz) using a BBI Broad Band Inverse 5 mm probe, or a Bruker AVIII (500 MHz) using a QNP (Quad Nucleus detect) 5 mm probe. Chemical shifts are expressed in ppm relative to an internal standard, tetramethylsilane (ppm = 0.00). The following abbreviations have been used: br = broad signal, s = singlet, d = doublet, dd = double doublet, t = triplet, td = triplet doublet, dddd = doublet doublet doublet doublet, q = quartet, m = multiplet, or any combination of.
Microwave reactor:
Microwave reactions were carried out using a Biotage® Initiator® in vials appropriate to the scale of the reaction and at the temperature and time described in the experimental details. Purification Equipment:
Purifications were carried out using pre-packed silica gel cartridges either on a Teledyne ISCO CombiFlash® or Biotage® Isolera Four® or using compressed air to apply external pressure. Solvents and gradients shown in the experimental details were used.
Reverse Phase High Pressure Liquid Chromatography (HPLC) was used to purify compounds where indicated. Separation using gradient elution on a Phenomenex Gemini CI 8 column (250 x 21.2 mm, 5 micron) as stationary phase and using mobile phase indicated, operating at a 18 mL/min flow rate using a Gilson UV/Vis -155 dual channel detector and Gilson GX-271 automated liquid handler.
Phase separator cartridges are supplied by Biotage® as Isolute® phase separator cartridges.
LIST OF ABBREVIATIONS
AcOH Acetic acid
AIBN 2,2 ' - Azobis(2-methylpropionitrile)
Atm. Atmosphere
BOC ieri-Butyloxycarbonyl group
(BOC)20 Di-ieri-butyl dicarbonate
CrOs Chromium(VI) oxide
CDC13 Deuterated chloroform
DavePhos 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl
DCM Dichloromethane / methylene chloride
DMA N,N-Dimethylacetamide
DIAD Diisopropyl azodicarboxylate
DIPEA DIPEA
DMAP 4-Dimethylaminopyridine
DME 1 ,2-Dimethoxyethane
DMF N,N-Dimethylformamide
DMSO Dimethyl sulfoxide
DPPF 1 , 1 '-Bis(diphenylphosphino)ferrocene
ES Electrospray
Et20 Diethyl ether
Et3N Triethylamine
EtOH Ethanol/Ethyl alcohol
EtOAc Ethyl acetate
H20 Water
H2S04 Sulfuric acid
HATU 2-( 1 Η-Ί- Azabenzotriazol- 1-yl)— 1 ,1,3 ,3 -tetramethyl uronium hexafluorophosphate methanaminium
HBTU 6>-Benzotriazol-l-yl-NN,N',N'-tetramethyluronium hexafluorophosphate
HC02H Formic acid
HC1 Hydrochloric acid HOBT 1 -Hydroxybenzotriazole
HPLC High pressure liquid chromatography
RP HPLC Reverse phase high pressure liquid chromatography
IBX 2-Iodoxybenzoic acid
IMS Industrial methylated spirit
KOH Potassium hydroxide
K2CO3 Potassium carbonate
LDA Lithium diisopropylamide
-PrOH Isopropanol / isopropyl alcohol / propan-2-ol
LCMS Liquid Chromatograph / Mass Spectroscopy
LiOH Lithium hydroxide
MgS04 Magnesium sulphate
MeOH Methanol / Methyl alcohol
MW Microwaves
NaH Sodium hydride
NaCl Sodium chloride
NaOH Sodium hydroxide
Na2S04 Sodium sulfate
Na2C03 Sodium carbonate
NaHC03 Sodium bicarbonate / Sodium hydrogen carbonate
NBS N-Bromosuccinimide
NH4C1 Ammonium chloride
NMP 1 -Methyl-2-pyrrolidinone
POCl3 Phosphorus oxychloride
PhCH3 Toluene
Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)
PSI Pound per square inch
RT Room temperature
sat. Saturated
SCX-2 Pre-packed Isolute® silica-based sorbent with a chemically bonded propylsulfonic acid functional group
SFC Supercritical fluid chromatography
TBDMS ieri-Butyldimethylsilyl
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TIPS Triisopropylsilyl
TLC Thin layer chromatography
TMSC1 Chlorotrimethylsilane
XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
Preparations 1 and 2: (3R)-3-Aminobutan-l-ol and (3S)-3-Aminobutan-l-ol
Figure imgf000041_0001
Figure imgf000041_0002
Step 1 3-rr(Benzyloxy)carbonyllaminolbutanoic acid
Into a 2000-mL 4-necked round-bottom flask was placed a solution of 3- aminobutanoic acid (100 g, 969.75 mmol, 1.00 equiv) in water (1000 mL), followed by the addition of potassium hydroxide (136 g, 2.42 mol, 2.50 equiv) in several batches. To this was added benzyl chloroformate (247 g, 1.45 mol, 1.50 equiv) dropwise with stirring at 0-5°C. The resulting solution was stirred at 25°C for 5 h. The reaction progress was monitored by LCMS. The resulting solution was extracted with 3x250 mL of dichloromethane and the aqueous layers were combined. The pH value of the water phase was adjusted to 3 with hydrogen chloride (2 mol/L). The precipitates were collected by filtration and dried to afford 102 g (44%) of 3- [[(benzyloxy)carbonyl]amino]butanoic acid as a white solid.
Step 2: Benzyl N-r(2.S')-4-hydroxybutan-2-yllcarbamate and Benzyl N-r(2i?)-4-hydroxybutan-2- yllcarbamate
Into a 2000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 3-[[(benzyloxy)carbonyl]amino]butanoic acid (102 g, 429.92 mmol, 1.00 equiv) in THF (300 mL), followed by the addition of BH3/THF (IN) (645 mL, 1.50 equiv) dropwise with stirring at 0-5°C. The resulting solution was stirred at 40°C for 2 h, quenched by the addition of 200 mL of methanol and concentrated under vacuum. The residue was purified on a silica gel column eluting with ethyl acetate: petroleum ether (1 :2). The crude product (70 g) was purified by Prep-SFC with the following conditions (prep SFC):
Column, Phenomenex Lux 5u Cellulose-4, 2.12*25,5um; mobile phase, C02 (85%), ethanol (15%); Detector, UV 254nm. This resulted in 30 g (31.5%) of benzyl N-[(2R)-4-hydroxybutan- 2-yl]carbamate as an off-white solid and 30 g (31.5%) of benzyl N-[(2S)-4-hydroxybutan-2- yl]carbamate as an off-white solid.
Step 3: (3i?)-3-Aminobutan-l-ol and (3^)-3-Aminobutan-l-ol
Into a 1000-mL round-bottom flask was placed a solution of benzyl N-[(2S)-4- hydroxybutan-2-yl] carbamate (30 g, 134.4 mmol, 1.00 equiv) in methanol (500 mL) and palladium carbon (3 g, 0.10 equiv). The resulting solution was stirred at 25°C for 12 h under an atmosphere of hydrogen. The solids were filtered out and the filtrate was concentrated under vacuum to afford 11.7 g (92%) of (35)-3-aminobutan-l-ol as an oil. lH NMR (300MHz, DMSO, ppm): δ 4.48 (3H, s), 3.47 (2H, s), 2.96 (1H, s), 1.47-1.41 (2H, q), 1.02-0.99 (3H, d); LCMS (ESI), m/z, 90 [M+H] +; measured [a]D 2a2 +11.65° (C=1.22g/100mL in EtOH), lit. [a]D 2° +16.3C (c=4.5 in EtOH) (J. Org. Chem. 1996, 61, 2293-2304.).
Using the above procedure, 12.0 g 12 g (94%) of (3ii)-3-aminobutan-l-ol was isolated as an oil. 1H NMR (300MHz, DMSO, ppm): δ 4.48 (3H, s), 3.47 (2H, s), 2.96 (1H, s), 1.47-1.41 (2H, q), 1.02-0.99 (3H, d); LCMS (ESI), m/z, 90 [M+H] +; measured [a]D 2a2 -11.1° (C = 0.32g/100mL in EtOH), lit. [a]D 25 -25° (c= 1.25 in EtOH) (Tetrahedron: Asymmetry 1999, 10, 2213-2224.).
Preparation 3 : (R)-N-(4-Chlorobutan-2- yl)- 1 - henylmethanesulfonamide
Figure imgf000042_0001
Step 1 : (i?)-3-(Phenylmethylsulfonamido)butyl phenylmethanesulfonate
To a solution of (3ii)-3-aminobutan-l-ol (1.0 g, 11.2 mmol) and triethylamine
(3.3 mL, 23.6 mmol) in tetrahydrofuran (37 mL) at 0 °C was slowly added
phenylmethanesulfonyl chloride (4.49 g, 23.6 mmol) and the reaction was stirred at room temperature for 16 hours. MTBE (100 mL) was then added and the Et3N HCl salt was removed by filtration. The filtrate was then concentrated to give crude (R)-3- (phenylmethylsulfonamido)butyl phenylmethanesulfonate which was used without purification. LCMS (ESI), m/z, 398 [M+H] +.
Step 2: (i?)-N-(4-Chlorobutan-2-yl)-l -phenylmethanesulfonamide To the crude (ii)-3-(phenylmethylsulfonamido)butyl phenylmethanesulfonate (23.6 mmol) was added sodium chloride (984 mg, 16.8 mmol) and dimethylformamide (37 mL) and the reaction was stirred at 80 °C for 16 hours. The reaction was then diluted with EtOAc, washed with water (x2) and brine, dried with MgS04, concentrated and purified by silica gel column chromatography (0-50% Acetone in Heptane, 216 nM) to give (ii)-N-(4-chlorobutan-2- yl)-l-phenylmethanesulfonamide (1.71 g, 6.53 mmol, 58% yield over 2 steps). LCMS (ESI), m/z, 261 [M+H] +.
Additional compounds made using the above procedure are shown in Table 1.
Table 1
Figure imgf000043_0002
Figure imgf000043_0001
K2CO3 (8.7 g, 62 mmol) was added into a mixture of phenylmethanesulfonyl chloride (6 g, 31 mmol) and 2-bromoethanamine hydrobromide (6.4 g, 31 mmol) in DCM (100 mL) at 0°C. And the resulting mixture was stirred at r.t. for 4 hours and left standing overnight. Upon the completion of reaction, water (100 mL) was added in and DCM phase was separated. The aqueous phase was extracted with DCM. The combined organic phase was dried over Na2S04, filetered and concentrated in vacuo to provide a crude which was separated with column chromatography (silica gel with 200 - 300 mesh, 0 to 50% of EtOAc in petroleum ether) to provide compound N-(2-bromoethyl)(phenyl)methanesulfonamide (7.0 g, 80%) as a pale yellow solid. 1H NMR (300 MHz, CDC13) δ 7.40 (m, 5H), 4.58 (m, 1H), 4.29 (s, 2H), 3.34-3.29 (m, 4H). LCMS (ESI), 300, 302 [M+Na]+, Br pattern found.
Preparation 8 N-(2-bromoethyl)(4-fluorophenyl)methanesulfonamide
Figure imgf000044_0001
N-(2-bromoethyl)(4-fluorophenyl)methanesulfonamide was also made using the above procedure, replacing phenylmethanesulfonyl chloride with 4-fluoro-phenylmethanesulfonyl chloride. XH NMR (300 MHz, CDC13) δ 7.43-7.38 (m, 2H), 7.13-7.07 (m, 2H), 4.62 (br s, 1H), 4.26 (s, 2H), 3.41-3.32 (m, 4H).
Preparation 9: N-(3-bromopropyl)(phenyl)methanesulfonamide
Figure imgf000044_0002
A solution of phenylmethanesulfonyl chloride (2.19 g, 10 mmol) was added into a suspension of 3-bromopropan-l -amine hydrobromide (2.19 g, 10 mmol) and Et3N (2.02 g, 20 mmol) in THF (50 mL) at 0 °C. The mixture was stirred at 0 °C for 5 min. TLC confirmed the completion of reaction. Solid was filtered out with suction, and the filtrate was concentrated to provide compound N-(3-bromopropyl)(phenyl)methanesulfonamide (2.7 g, quant.) as a pale yellow solid which was used in the next step without further purification. XH NMR (300 MHz,
CDC13) δ 7.40 (m, 5H), 4.48 (m, 1H), 4.27 (s, 2H), 3.41 (t, J = 6.6 Hz, 2H), 3.16 (q, 2H), 2.01 (m, 2H). LCMS (ESI), m/z, 314 and 316 [M+Na]+, Br pattern found.
Preparation 10: N-(3-bromopropyl)(4-fluorophenyl)methanesulfonamide
Figure imgf000044_0003
N-(3-bromopropyl)(4-fluorophenyl)methanesulfonamide was prepared using the above procedure. 1H NMR (300 MHz, CDC13) δ 7.42-7.37 (m, 2H), 7.13-7.07 (m, 2H), 4.26 (m, 1H), 4.24 (s, 2H), 3.46-3.42 (m, 2H), 3.20-3.16 (m, 2H), 2.05-2.00 (m, 2H).
Preparation 11 : 6-Phenyl-l,2-thiazinane 1 ,1 -dioxide
Figure imgf000045_0001
To a solution of N-(3-bromopropyl)-l-phenylmethanesulfonamide (2.3 g, 7.9 mmol), diisopropylamine (0.28 mL, 2.0 mmol) and 1,10-phenanthroline (3.6 mg, 0.02 mmol) in tetrahydrofuran (26 mL) at -78 °C was added n-BuLi (6.8 mL, 2.5 M in hexanes) dropwise and the reaction was stirred for 16 hours. Saturated NH4C1 was then added and the reaction was diluted with EtOAc, washed with water and brine, dried with MgS04, concentrated and purified by silica gel column chromatography (0-50% EtO Ac/heptane) to 6-Phenyl-l,2-thiazinane 1,1- dioxide (1.3 g, 80% yield). XH NMR (300 MHz, DMSO-J6) δ 7.40-7.35 (m, 5H), 6.98 (m, 1H), 4.12 (dd, 1H), 3.26-3.20 (m, 2H), 2.40-2.30 (m, 1H), 2.16-2.12 (m, 1H), 1.77-1.65 (m, 2H). LCMS (ESI), m/z, 234 [M+Na]+. (Reference: D. Askin, et al. Org. Lett. 2003, 4175.)
Additional compounds made using the above procedure are shown in Table 2.
Table 2
Figure imgf000045_0002
°w° 7 -phenyl- 1 ,2-thiazepane 1 , 1 -dioxide
18 226
Preparation 19: 3-Phenyl-l,4,5-oxathiazepane 4,4-dioxide
Figure imgf000046_0001
Step 1 : N-(2-((Tert-butyldimethylsilyl)oxy)ethyl)- 1 -phenylmethanesulfonamide
To a solution of 2-((tert-butyldimethylsilyl)oxy)ethanamine (11.7 g, 66.6 mmol) and triethylamine (11.2 mL, 79.9 mmol) in tetrahydrofuran (222 mL) at 0 °C was slowly added phenylmethanesulfonyl chloride (12.7 g, 66.6 mmol) portion wise and the reaction was stirred at room temperature for 16 hours. MTBE was then added and the Et3N HCl salt was removed by filtration. The filtrate was then concentrated and purified by silica gel solumn chromatography (0-30% Acetone in heptane, 216 nM) to N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-l- phenylmethanesulfonamide (17.8 g, 81 % yield). LCMS (ESI), m/z, 330. [M+H] +.
Step 2: N-(2-((Tert-butyldimethylsilyl)oxy)ethyl)- 1 -phenylethenesulfonamid
To a solution of N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-l-phenyl- methanesulfonamide (33 g, 100.2 mmol) in tetrahydrofuran (334 mL) at -78 °C was slowly added n-BuLi (2.5 M in hexanes) (100 mL, 250 mmol) via cannula and the reaction was stirred at -78 °C was 2 hours. Chloroiodomethane (8.3 mL, 110 mmol) was then slowly added and the reaction was stirred at -78 °C for one hour, then allowed to warm to room temperature and aged for 16 hours. The reaction was then quenched with saturated NH4C1 and extracted with dichloromethane, dried with MgS04, concentrated and purified by silica gel column chromatography (0-60% EtOAc in heptane) to give N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-l- phenyl-ethenesulfonamide (24 g, 70 % yield). LCMS (ESI), m/z, 342. [M+H] +.
Step 3: 3-Phenyl-l,4,5-oxathiazepane 4,4-dioxide
To a solution of N-(2-((Tert-butyldimethylsilyl)oxy)ethyl)-l- phenylethenesulfonamide (717 mg, 2.1 mmol) in tetrahydrofuran (7 mL) at 0 °C was added tetrabutylammonium fluoride (1.0 M in THF) (2.2 mL, 2.2 mmol) dropwise and the reaction was stirred at room temperature for 16 hours. Saturated NH4CI was then added and the product was extracted with dichloromethane (x2), dried with MgS04, concentrated and purified by silica gel column chromatography (0-100% EtOAc in heptane) to give 3-phenyl-l,4,5-oxathiazepane 4,4-dioxide (401 mg, 84 % yield). (24 g, 70 % yield). LCMS (ESI), m/z, 228. [M+H] +.
(Reference: P. Hansen, et al. Org. Lett. 2008, 2951).
Additional compounds made using the above procedure are shown in Table 3.
Table 3
Figure imgf000047_0001
Preparation 24 2-(4-Bromo-2-fluorobenzyl)-6-phenyl-l,2-thiazinane 1,1 -dioxide
Figure imgf000048_0001
To a solution of 6-phenyl-l,2-thiazinane 1,1 -dioxide (300 mg, 1.42 mmol) and 4- bromo-l-(bromomethyl)-2-fluorobenzene (456 mg, 1.7 mmol) in N,N-dimethylacetamide (5 mL) at 0 °C was added sodium hydride (60% in mineral oil) (68 mg, 1.85 mmol) and the reaction was stirred at room temperature for 2 hours. Water was added and the reaction was diluted with EtOAc, washed with brine, dried with MgS04, filtered and purified by silica gel column chromatography (0-60% EtOAc/heptane) to give 2-(4-bromo-2-fluorobenzyl)-6-phenyl- 1 ,2-thiazinane 1 ,1 -dioxide as a mixture of diastereomers (396 mg, 70% yield). LCMS (ESI), m/z, 398 [M+H] +.
Similarly prepared was (3S)-2-(4-bromo-2-fluorobenzyl)-3-methyl-6-phenyl-l,2- thiazinane 1 , 1 -dioxide.
Intermediate 1 : (3^,6i?)-2-(4-Bromo-2,5-difluorobenzyl)-3-methyl-6-phenyl-l,2-thiazinane 1,1- dioxide
Figure imgf000048_0002
A 3 L flask was mounted with a mechanical stirrer and was charged with (3S,6R)-3- methyl-6-phenyl-thiazinane 1,1-dioxide (100 g, 444 mmol), l-bromo-4-(chloromethyl)-2,5- difluorobenzene (122 g, 488 mmol) in N,N-dimethylformamide (800 mL) under a nitrogen atmosphere and the solution was cooled to 0 °C. Under mechanical stirring, sodium hydride (60% in mineral oil, 18.6 g, 466 mmol) was added in small portions and the reaction was stirred at 0 °C for 30 minutes before being allowed to warm to RT. The reaction was further stirred at that temperature for an additional 2 h. Water (1.5 L) was then added and the precipitate was collected by filtration and dried under vacuum for 16 h to give crude material. The precipitate was suspended into 2.5 L of heptane: ethyl acetate: methanol (1 : 1 :0.5) and the suspension was heated at reflux. Acetone (100 mL) was then added to complete the dissolution of the material, and the solution was slowly cooled down to room temperature over 1 hour and then stored at -23 °C for 16 hours. The resulting crystals were collected by filtration to give the title compound (145 g, 76% yield). 1H NMR (400 MHz, DMSO-J6) δ 7.71 (dd, J = 9.2, 5.6 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.44 - 7.33 (m, 4H), 4.58 (dd, / = 12.8, 3.5 Hz, 1H), 4.51 (d, / = 17.9 Hz, 1H), 4.37 (d, J = 17.8 Hz, 1H), 4.20 - 4.06 (m, 1H), 2.48 - 2.38 (m, 1H), 2.15 - 2.07 (m, 1H), 1.90 - 1.73 (m, 1H), 1.72 - 1.62 (m, 1H), 1.12 (d, J = 6.8 Hz, 3H).
Intermediate 2: tert-Buty\ 2-r2,5-difluoro-4-rr(3^',6i?)-3-methyl-lJ-dioxo-6-phenyl-thiazinan-2- yll methyllphenyll acetate
Figure imgf000049_0001
A vial was charged with intermediate 1 (500 mg, 1.16 mmol),
bis(dibenzylidene)palladium (0.05 equiv., 0.058 mmol) and l,2,3,4,5-pentaphenyl-l'-(di-tert- butylphosphino)ferrocene (0.05 equiv., 0.058 mmol) and the vial was purged with nitrogen for 2 min. THF (2 mL) and 2-ier/-butoxy-2-oxoethylzinc chloride (0.5 M in Et20, 3.0 mL, 1.51 mmol) were then added and the reaction was stirred at RT for 4 h. Upon completion, the reaction was quenched with saturated aqueous NH4C1 and extracted with DCM (10 x 2 mL), dried with MgS04, filtered, concentrated, and purified by silica gel column chromatography (0% to 60% acetone in heptane) to give the title compound (534 mg, 99% yield). lU NMR (400 MHz,
CDCI3) δ 7.50 7.43 (m, 2H), 7.43 7.33 (m, 4H), 6.94 (dd, J = 10.0, 5.8 Hz, 1H), 4.52 (d, J = 17.0 Hz, 1H), 4.39 (d, J = 17.1 Hz, 1H), 4.33 4.20 (m, 1H), 3.98 (dd, J = 13.0, 3.5 Hz, 1H), 3.53 (s, 2H), 2.74 2.58 (m, 1H), 2.28-2.18 (m, 1H), 1.81 1.72 (m, 2H), 1.44 (s, 9H), 1.14 (d, J = 6.9 Hz, 3H).
Intermediate 3 : Γ2,5 -Difluoro-4-((3 6i?)-3 -methyl- 1 , 1 -dioxo-6-phenyl- 1 lambda*6* -
Figure imgf000049_0002
Step 1 : r2,5-Difluoro-4-((3^',6i?)-3-methyl-l ,l-dioxo-6-phenyl-llambda*6*-ri,21thiazinan-2- ylmethyP-phenyll-acetic acid
A mixture of intermediate 2 (300 mg, 0.64 mmol) and -toluene sulfonic acid
monohydrate (25 mg, 0.13 mmol) in PI1CH3 (15 mL) was stirred and heated at 90 °C. Solvent was removed in vacuo after 1.5 h and the residue triturated with H20. Solids were removed by filtration, washed with H20, and dried over MgS04 to give the title compound as a white solid (245 mg, 93% yield). 1H NMR (300 MHz, CDC13) δ 7.49-7.34 (6H, m), 7.00-6.92 (1H, m), 4.52 (1H, d, / = 17.2 Hz), 4.39 (1H, d, / = 17.1 Hz), 4.33 - 4.19 (1H, m), 3.98 (1H, dd, / = 12.9, 3.5 Hz), 3.67 (2H, s), 2.73-2.56 (1H, m), 2.28-2.17 (1H, m), 1.82-1.71 (2H, m), 1.14 (3H, d, / = 6.9 Hz). LCMS (Method A): m/z = 432 [M+Na]+.
Step 2: r2,5-Difluoro-4-((3^',6i?)-3-methyl-l,l-dioxo-6-phenyl-llambda*6*-ri,21thiazinan-2- ylmethyP-phenyll-acetic acid methyl ester
A stirred solution of the product from Step 1 (1.0 g, 2.2 mmol) in DCM (15 mL) at RT under argon was treated with DMF (1 drop) followed by oxalyl chloride (220 μL·, 2.6 mmol). After 1 h, the solvent was removed in vacuo and the resultant solid re-dissolved in DCM (5 mL) and added dropwise to anhydrous MeOH (10 mL). After stirring for 0.5 h, the solvent was removed in vacuo and the resulting solid triturated with ether and filtered to give the title compound as a beige solid (780 mg, 84% yield, 2 steps). Ή NMR (300 MHz, CDC13) δ 7.49- 7.43 (2H), 7.41-7.36 (3H, m), 6.99-6.93 (2H, m), 4.46 (2H, dd, / = 16.6, 39.9), 4.26 (1H, m), 3.99 (1H, dd, / = 3.7, 13.0 Hz), 3.72 (3H, s), 3.62 (2H, s), 2.65 (1H, m), 2.23 (1H, m), 1.77 (2H, m), 1.15 (3H, d, .7 = 7.3 Hz).
Intermediate 4: 2-r2,5-difluoro-4-((3^',6i?)-3-methyl-lJ-dioxo-6-phenyl-llambda*6*- ri,21thiazinan-2-ylmethyl)-phenyll-3-oxetan-3-yl-propionic acid methyl ester
Figure imgf000050_0001
A vial was charged with intermediate 3 (150 mg, 0.32 mmol) and DMF (1.5 mL), cooled to 0 °C and sodium hydride (60% in mineral oil, 18 mg, 0.45 mmol) was added. The solution was stirred at that temperature for 15 min and 3-(bromomethyl)oxetane (61 mg, 0.40 mmol) was subsequently added. The reaction was then warmed to RT and stirred at that temperature for 4 h. Saturated aqueous NH4C1 (15 mL) was added and the product was extracted with EtOAc (2 x 15 mL), dried with MgS04, filtered, concentrated, and purified by silica gel column chromatography (0% to 100% acetone in heptane) to give the title compound (86 mg, 50% yield). LCMS (ESI): m/z = 536.5 [M+H]+.
Intermediate 5 : Γ2.5 -Difluoro-4-((3 ',6 -3 -methyl- 1 , 1 -dioxo-6-phenyl- 1 lambda*6* - ri,21thiazinan-2-ylmethyl)-phenyll-oxetan-3-yl-acetic acid methyl ester
Figure imgf000051_0001
Step 1: Diazo-r2,5-difluoro-4-((3^,6i?)-3-methyl-l J-dioxo-6-phenyl-llambda*6*-ri,21thiazinan- 2-ylmethyl)-phenyll-acetic acid methyl ester
To a stirred solution of intermediate 3 (0.360 g, 0.85 mmol) and
-acetamidobenzenesulfonyl azide (0.245 g, 1.02 mmol) in CH3CN (8 mL) under argon, was added DBU dropwise (0.18 mL, 1.2 mmol). The reaction was stirred for 4 h, concentrated in vacuo and purified by purified by silica gel column chromatography (5% to 40%
EtOAc/cyclohexane) to give the title compound as a yellow solid (0.350 g, 92% yield).
Step 2: r2,5-Difluoro-4-((3^',6i?)-3-methyl-lJ-dioxo-6-phenyl-llambda*6*-ri,21thiazinan-2- ylmethyl)-phenyll-oxetan-3-yl-acetic acid methyl ester
To a degassed solution of 3 -hydroxy oxetane (0.065 g, 0.88mmol) and Rh(OAc)4 (9 mg, 0.02 mmol) under argon, was added dropwise, a degassed solution of the product from Step 1 (0.200 g, 0.44 mmol) in DCM (3 mL). The green solution was stirred for 1 h, concentrated in vacuo and purified by silica gel column chromatography (7% to 40% EtOAc/cyclohexane) to give the title compound (Product A) together with a by-product (Product B) (combined yield: 0.180 g, A:B-2.5:1). LC/MS (Method A): Product A, m/z, 518 [M+Na]+; Product B, m/z, 462 [M+Na]+.
Examples 1 and 2: (2i?)-2-r2,5-difluoro-4-rr(3^',6i?)-3-methyl-lJ-dioxo-6-phenyl-thiazinan-2- yHmethyHphenyH-2-(oxetan-3-yloxy)acetamide and (2£)-2-r2,5-difluoro-4-rr(3£,6i?)-3-methyl-
Figure imgf000051_0002
Intermediate 5 (110 mg, 0.22 mmol) was allowed to stand in 7 N NH3-MeOH (5 mL) for 6 d, concentrated in vacuo and the residue purified by silica gel column chromatography (DCM to 2.5% MeOH-DCM) to give the title compounds as a foam which were separated by SFC. First eluting title compound: Ή NMR (400 MHz, DMSO-J6) δ 7.63 (1H, s), 7.48 - 7.33 (6H, m), 7.25 - 7.18 (2H, m), 4.89 - 4.88 (1H, m), 4.64 - 4.46 (6H, m), 4.38 - 4.26 (2H, m), 4.13 - 4.04 (1H, m), 2.42 - 2.40 (1H, m), 2.11 - 2.04 (1H, m), 1.84 - 1.71 (1H, m), 1.64 (1H, dd, J=2.1, 14.2 Hz), 1.09 (3H, d, J=6.8 Hz); LCMS (ESI): m/z = 479.2 [M+H]+. Second eluting title compound: Ή NMR (400 MHz, DMSO-Je) δ 7.66 - 7.62 (1H, m), 7.48 - 7.33 (6H, m), 7.25 - 7.18 (2H, m), 4.89 (1H, s), 4.64 - 4.45 (6H, m), 4.38 - 4.26 (2H, m), 4.14 - 4.04 (1H, m), 2.45 - 2.35 (1H, m), 2.11 - 2.04 (1H, m), 1.84 - 1.60 (2H, m), 1.08 (3H, d, J=6.9 Hz; LCMS (ESI): m/z = 479.2 [M+H]+.
Examples 3 and 4: (35.6R)-2-rr2.5-difluoro-4-rf35.4R)-3-fluoro-4-(1.2.4-triazol-4-yl)-l- piperidyllphenyllmethyll-3-methyl-6-phenyl-thiazinane lj-dioxide and (3^,6^)-2-ΓΓ2,5- difluoro-4 (3i?,4^)-3-fluoro-4-(l,2,4-triazol-4-yl)-l-piperidyllphenyllmethyll-3-methyl-6- phenyl-thiazinane 1,1 -dioxide
Figure imgf000052_0001
Step 1: 3-Fluoro-4-rL2,41triazol-4-yl-piperidine-l-carboxylic acid tert-butylester
A mixture of 4-amino-3-fluoro-piperidine-l-carboxylic acid tert-buty\ ester (1.0 g, 4.6 mmol), N-[(E)-dimethylamino)N,N-dimethylformamide (3.26 g, 23 mmol) and -toluene sulfonic acid (92 mg, 0.46 mmol) in PhCH3 (30 mL) was heated at 110 °C for 20 h. The cooled reaction was diluted with CH2CI2 and washed with 5% (v/v) aqueous AcOH (50 mL). The aquesous phase was extracted with CH2CI2 and the combined organic extracts were dried over MgS04, filtered, concentrated in vacuo and purified by silica gel column chromatography (EtOAc to 10% MeOH-EtOAc) to give the title compound as a colourless oil (650 mg). Ή NMR (300 MHz, CDC13) δ 8.28 (2H, d, J=1.4 Hz), 4.88 - 4.24 (4H, m), 3.49 (9H, s), 3.15 - 2.99 (1H, m), 2.93 - 2.85 (1H, m), 2.42 - 2.26 (1H, m), 1.94 (1H, dd, J=3.0, 12.9 Hz).
Step 2: 3-Fluoro-4-rL2,41triazol-4-yl-piperidine
To a solution of the product from step 1 (650 mg) in 1,4-dioxane (5 mL) was added 4 N HCl in 1,4-dioxane (10 mL). The reaction was allowed to stand for 0.25 h and MeOH was added (5 mL). After 0.25 h the reaction was concentrated in vacuo and the residue purified by SCX column using MeOH-H20 then 2 N NH3-MeOH to give the title compound as a white solid (355 mg). Step 3: (35,6R)-2-rr2,5-difluoro-4-r(35,4R)-3-fluoro-4-(l ,2,4-triazol-4-yl)-l- piperidyllphenyllmethyll-3-methyl-6-phenyl-thiazinane 1,1-dioxide and (3£,6^)-2-ΓΓ2,5- difluoro-4 (3i?^^)-3-fluoro-4-(l,2^ riazol-4-yl) -piperidyllphenyllmethyll-3-methyl-6- phenyl-thiazinane 1,1 -dioxide
Two parallel reactions containing a mixture of the product from step 2 (152 mg, 0.89 mmol), intermediate 1 (250 mg, 0.57 mmol), Xanthphos (67 mg), Pd(OAc)2 (13 mg), CS2CO3 (1.13g, 3.45 mmol) and 1 ,4-dioxane (10 mL) were heated at 100 °C for 5 h. The cooled reactions were diluted with H20 and washed with EtOAc, dried over MgS04, filtered, and concentrated in vacuo to give the title compounds after separation by SFC and crystallization (CH3CN). First eluting title compound: Ή NMR (400 MHz, DMSO-J6) δ 8.60 - 8.59 (2H, m), 7.46 - 7.34 (6H, m), 7.15 (1H, dd, J=7.0, 13.3 Hz), 6.96 - 6.89 (1H, m), 4.75 - 4.61 (1H, m), 4.52 - 4.38 (2H, m), 4.28 (1H, d, J=17.3 Hz), 4.11 - 4.04 (1H, m), 3.81 - 3.72 (1H, m), 3.56 (1H, d, J=13.0 Hz), 3.18 - 3.11 (1H, m), 2.92 (1H, dd, J=10.7, 12.5 Hz), 2.45 - 2.35 (2H, m), 2.11 - 1.95 (2H, m), 1.84 - 1.71 (1H, m), 1.63 (1H, dd, J=2.3, 14.1 Hz), 1.08 (3H, d, J=6.9 Hz); LCMS (ESI): m/z = 520.1 [M+H]+. Second eluting title compound: Ή NMR (400 MHz, DMSO-J6) δ 8.60 - 8.59 (2H, m), 7.46 - 7.34 (6H, m), 7.15 (1H, dd, J=7.0, 13.3 Hz), 6.96 - 6.89 (1H, m), 4.75 - 4.61 (1H, m), 4.52 - 4.38 (2H, m), 4.28 (1H, d, J=17.3 Hz), 4.11 - 4.04 (1H, m), 3.81 - 3.72 (1H, m), 3.56 (1H, d, J=13.0 Hz), 3.18 - 3.11 (1H, m), 2.92 (1H, dd, J=10.7, 12.5 Hz), 2.45 - 2.35 (2H, m), 2.11 - 1.95 (2H, m), 1.84 - 1.71 (1H, m), 1.63 (1H, dd, J=2.3, 14.1 Hz), 1.08 (3H, d, J=6.9 Hz); LCMS (ESI): m/z = 520.1 [M+H]+.
Examples 5 and 6: (2.S')-2-r2,5-difluoro-4-rr(3^',6i?)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yllmethyllphenyll-3-(oxetan-3-yl)propanamide and (2i?)-2-r2,5-difluoro-4-rr(3£,6i?)-3-methyl- l,l-dioxo-6-phenyl-thiazinan-2-yllmethyllphenyll-3-(oxetan-3-yl)propanamide and (2i?)-2-T2,5- difluoro-4-rr(3^',6i?)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yllmethyllphenyll-3-(oxetan-3- yPpropanamide
Figure imgf000053_0001
A mixture of intermediate 4 (110 mg, 0.22 mmol) in 7 N NH3-MeOH (5 mL) was allowed to stir for 6 d. The reaction was concentrated in vacuo and purified by silica gel column chromatography (CH2C12 to 2.5% MeOH-CH2Cl2) followed by SFC to give the title compounds. First eluting title compound: Ή NMR (400 MHz, DMSO-J6) δ 7.54 - 7.50 (1H, m), 7.45 - 7.33 (6H, m), 7.27 - 7.14 (2H, m), 6.99 (1H, s), 4.56 - 4.43 (4H, m), 4.36 - 4.22 (2H, m), 4.13 - 4.07 (2H, m), 2.86 - 2.76 (1H, m), 2.45 - 2.35 (1H, m), 2.26 - 2.16 (1H, m), 2.11 - 2.03 (1H, m), 1.97 - 1.88 (1H, m), 1.84 - 1.71 (1H, m), 1.67 - 1.60 (1H, m), 1.08 (3H, d, J=6.9 Hz); LCMS (ESI): m/z = 479.2 [M+H]+. Second eluting title compound: Ή NMR (400 MHz, DMSO-J6) δ 7.54 - 7.50 (1H, m), 7.45 - 7.33 (6H, m), 7.27 - 7.14 (2H, m), 6.99 (1H, s), 4.56 - 4.43 (4H, m), 4.36 - 4.22 (2H, m), 4.13 - 4.07 (2H, m), 2.86 - 2.76 (1H, m), 2.45 - 2.35 (1H, m), 2.26 - 2.16 (1H, m), 2.11 - 2.03 (1H, m), 1.97 - 1.88 (1H, m), 1.84 - 1.71 (1H, m), 1.67 - 1.60 (1H, m), 1.08 (3H, d, J=6.9 Hz); LCMS (ESI): m/z = 479.2 [M+H]+.
Example 7: l-r2,5-difluoro-4-rr(3^',6i?)-3-methyl-lJ-dioxo-6-phenyl-thiazinan-2- yllmethyllphenyll-3-hydroxy-3-(trifluoromethyl)cyclobutanecarboxamide
Figure imgf000054_0001
Step 1: (2,5-Difluoro-4-methylphenyl)methanol
To a solution of 2,5-difluoro-4-methylbenzoic acid (17.2 g, 99.92 mmol) in THF (80 mL) was added dropwise borane-tetrahydrofuran complex (200 mL, 200 mmol) at 0 °C over 30 min, then the mixture was heated at 60 °C for 2 h. The reaction was cooled to RT and the reaction was quenched with brine. The resulting mixture was poured into water, extracted with EtOAc (2 x 100 mL). The organic extracts were combined and washed with brine (2 x 50 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleumn ether/EtOAc (3/1) as eluting solvents to afford the title compound as a white solid. (15.5 g, 98% yield). LCMS (ESI): m/z = 141.2 [M-OH]+.
Step 2: l-(Chloromethyl)-2,5-difluoro-4-methylbenzene
A mixture of (2,5-difluoro-4-methylphenyl)methanol (15.5 g, 98.1 mmol) in SOCl2 (60 mL) was stirred at RT for 12 h. The solvent was removed under reduced pressure to obtain the crude product as yellow oil (16 g, 93% yield). The crude compound was used in next step without further purification.
Step 3: 2-(2,5-Difluoro-4-methylphenyl)acetonitrile
A mixture of l-(chloromethyl)-2,5-difluoro-4-methylbenzene (18 g, 102.3 mmol), NaCN (30.1 g, 613.6 mmol) and TBAB (3.29 g, 10.2 mmol) in DCM/water (1: 1, 240 mL) were stirred at RT for 12 h. The reaction was poured into water (150 mL) and extracted with DCM
(2 x 100 mL). The combined extracts were washed with brine (2 x 50 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleumn ether/EtOAc (3/1) as eluting solvents to afford the title compound as a yellow solid. (16.4 g, 96% yield). LCMS (ESI): m/z = 168.1 [M+H]+.
Step 4: l-(2,5-Difluoro-4-methylphenyl)-3,3-dimethoxycyclobutanecarbonitrile
To a solution of 2-(2,5-difluoro-4-methylphenyl)acetonitrile (16.7 g, 100 mmol) in
DMSO (200 mL) was added NaH (8 g, 200 mmol, 60% oil dispersion), portion-wise, at RT. The reaction was stirred for 1 h at RT, and then l,3-dibromo-2,2-dimethoxypropane (39.3 g, 150 mmol) was added. The mixture was heated at 60 °C for 6 h. The reaction was quenched with water (100 mL) at 0 °C and extracted with EtOAc (2 x 100 mL). The organic extracts were combined and washed with brine (2 x 50 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleumn ether/EtOAc (4/1) as eluting solvents to afford the title compound as a yellow solid (12 g, 45% yield). XH NMR(400 MHz, DMSO-J6) 5 7.36-7.28(m, 2H), 3.18(s, 3H), 3.05(s, 3H), 3.03 (d, J = 13.6 Hz, 2H), 2.77 (d, J = 13.6 Hz, 2H), 2.24 (d, J = 1.6 Hz, 3H). LCMS (ESI): m/z = 268.0 [M+H]+.
Step 5: l-(2,5-Difluoro-4-methylphenyl)-3,3-dimethoxycyclobutanecarboxylic acid A solution of l-(2,5-difluoro-4-methylphenyl)-3,3-dimethoxycyclobutanecarbonitrile (6.7 g, 25.1 mmol) and KOH (50% aqueous, 15 g) in n-BuOH (30 ml) were heated at 125 °C for 16 h. The reaction mixture was concentrated under reduced pressure. Water (100 mL) was added and extracted with EtOAc (2 x 100 mL). The aqueous phase was adjusted to pH~2 with aqueous 2N HC1 and extracted with EtOAc (3 x 100 mL). The organic phase was dried over Na2S04, filtered, and concentrated under reduced pressure to obtain the title product as a yellow solid (6.2 g, 86% yield). The crude product was used in next step without further purification. LCMS (ESI): m/z = 309.0 [M+Na]+.
Step 6: Methyl l-(2,5-difluoro-4-methylphenyl)-3,3-dimethoxycyclobutane-l- carboxylate
To a solution of l-(2,5-difluoro-4-methylphenyl)-3,3-dimethoxycyclobutanecarboxylic acid (6 g, 21 mmol) in methanol (25 mL) was added SOCl2 (3.74 g, 31.5 mmol), and the reaction mixture was stirred at RT for 12 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography using petroleumn ether/EtOAc (8/1) as eluting solvents to afford the title compound as light yellow oil (5.5 g, 87% yield). lU NMR(400 MHz, DMSO-J6) 5 7.22(dd, / = 10 Hz, / = 6.4 Hz, 1H), 7.13(dd, / = 11.2 Hz, / = 6.4 Hz, 1H), 3.58(s, 3H), 3.07(s, 3H), 3.02(s, 3H), 2.93(d, J = 13.2 Hz, 2H), 2.59 (d, J = 12.8 Hz, 2H), 2.21 (d, J = 1.6 Hz, 3H). LCMS (ESI): m/z = 323.0 [M+Na]+.
Step 7: l-(4-Bromomethyl-2,5-difluoro-phenyl)-3,3-dimethoxy-cyclobutanecarboxylic acid methyl ester
A solution of l-(2,5-difluoro-4-methyl-phenyl)-3,3-dimethoxy-cyclobutanecarboxylic acid methyl ester (3.0 g, 10.0 mmol) in CHC13 (100 mL) was treated with NBS (2.13 g, 12.0 mmol) followed by benzoyl peroxide (165 mg, 0.68 mmol) and the solution refluxed for 2 h. The reaction was concentrated in vacuo and purified by silica gel column chromatography (cyclohexane - EtOAc/cyclohexane 1 :3) to give the title compound as a yellow oil (3.0 g). LCMS (ESI): m/z = 479.2 [M+H]+.
Step 8: l-r2.5-Difluoro-4-((3tS'.6^)-3-methyl-l.l-dioxo-6-phenyl-llambda*6*-ri.21thiazinan-2- ylmethyl)-phenyll-3,3-dimethoxy-cyclobutanecarboxylic acid methyl ester
A mixture of the product from step 7 (3.0 g, 7.9 mmol), (35',6ii)-3-methyl-6-phenyl- thiazinane 1 ,1-dioxide (1.2g, 5.3 mmol), cesium carbonate (2.3g, 7.5 mmol), and anhydrous DMF (20 mL) was stirred at RT for 16 h. The reaction was diluted with EtOAc (150 mL) and washed with H20 (150 mL) then brine (100 mL), dried over MgS04, evaporated and purified using flash chromatography (EtOAc/cyclohexane 1:4 - 1:2) to give the title compound as a yellow oil (2.9 g).
Step 9: l-r2,5-Difluoro-4-((3tS',6^)-3-methyl-l,l-dioxo-6-phenyl-llambda*6*-ri,21thiazinan-2- ylmethyl)-phenyll-3-oxo-cyclobutanecarboxylic acid methylester
A solution of the product from step 8 (2.9 g) in acetone (100 mL) was treated with cone.
H2SO4 (5 drops). The solution was refluxed for 45 min and H20 was added to the hot solution until a precipitate started to form. On evaporation of some of the solvent, a white solid was obtained which was collected by filtration to give the title compound as an off-white solid (1.7 g). Ή NMR (300 MHz, CDC13) δ 7.50 - 7.36 (6H, m), 6.94 (1H, dd, .7=6.2, 10.1 Hz), 4.49 (2H, dd, .7=15.3, 41.5 Hz), 4.28 - 4.25 (1H, m), 4.00 (1H, dd, .7=3.4, 12.9 Hz), 3.91 - 3.81 (2H, m), 3.74 - 3.73 (3H, m), 3.51 (2H, dd, .7=2.6, 17.0 Hz), 2.74 - 2.58 (1H, m), 2.29 - 2.16 (1H, m), 1.84 - 1.73 (2H, m), 1.17 (3H, d, .7=7.0 Hz). LCMS (ESI), m/z, 500 [M+Na]+.
Step 10: l-r2,5-Difluoro-4-((3tS',6^)-3-methyl-l,l-dioxo-6-phenyl-llambda*6*-ri,21thiazinan-2- ylmethyl)-phenyll-3-hydroxy-3-trifluoromethyl-cyclobutanecarboxylic acid methyl ester
A solution of the product from step 9 (0.5 g, 1.05 mmol) in THF (4 mL) was stirred at -
78 °C and treated with trifluoromethyltrimethylsilane (208 mg, 1.47 mmol) and then cesium fluoride (475 mg, 3.14 mmol). After stirring for 1 h at -78 °C the reaction was allowed to warm to RT. A further portion of cesium fluoride (475 mg, 3.14 mmol) was added and stirring continued for 0.5 h. The reaction was quenched with EtOH, stirred for 0.5 h then diluted with EtOAc (70 mL) and brine (50 mL). The organic phase was dried (Na2S04), filtered, concentrated in vacuo and purified using flash chromatography to give the title compound (499 mg). LCMS (ESI): m/z = 548 [M+H]+.
Step 11 : trans 1 2,5-Difluoro-4-((35,6R)-3-methyl-l J-dioxo-6-phenyl-llambda*6*-ri,2 lthiazinan-2-ylmethyl)-phenyll-3-hydroxy-3-trifluoromethyl-cyclobutanecarboxylic acid methyl est
To a solution of the product from step 10 (0.5 g, 0.914 mmol) in THF (8 mL) was added H20 (8 mL), followed by lithium hydroxide (44 mg) and the reaction left to stir for 1.5 h. The reaction as diluted with EtOAc and H20 and the organic phase separated and dried (Na2S04), filtered, concentrated in vacuo and purified using flash chromatography (0-50% EtOAc- cyclohexanes) to give the title compound as an oil (220 mg). The aqueous phase was acidified using 1 N HC1, extracted with EtOAc, dried (Na2S04), filtered and concentrated in vacuo to provide cis l-[2,5-difluoro-4-((3.S',6ii)-3-methyl-l ,l-dioxo-6-phenyl-llambda*6*-[l,2]thiazinan- 2-ylmethyl)-phenyl]-3-hydroxy-3-trifluoromethyl-cyclobutane carboxylate.
Step 12: l-r2,5-Difluoro-4-((3tS',6^)-3-methyl-l,l-dioxo-6-phenyl-llambda*6*-ri,21thiazinan-2- ylmethyl)-phenyll-3-hydroxy-3-trifluoromethyl-cyclobutanecarboxylic acid
A solution of the product from step 11 (220 mg) in MeOH (2 mL) was treated with H20
(2 mL) and NaOH (80 mg) and the reaction heated at 50 °C for 9 h. The cooled reaction was neutralized with 1 N aqueous HC1, extracted into EtOAc, dried (Na2S04), filtered, and concentrated in vacuo to give the title compound (200 mg). Ή NMR (400 MHz, DMSO-J6) δ 7.50 - 7.24 (6H, m), 6.73 (1H, s), 4.62 - 4.52 (2H, m), 4.40 (1H, d, J=17.9 Hz), 4.17 - 4.09 (1H, m), 3.17 (1H, s), 2.84 (2H, d, J=14.0 Hz), 2.48 - 2.39 (2H, m), 2.13 - 2.08 (1H, m), 1.85 - 1.64 (2H, m), 1.15 (3H, d, J=6.9 Hz); LCMS (ESI): m/z = 574 [M+H]+.
Step 13: l-r2,5-difluoro-4-rr(3^',6i?)-3-methyl-l J-dioxo-6-phenyl-thiazinan-2- yllmethyllphenyll-3-hydroxy-3-(trifluoromethyl)cvclobutanecarboxamide
To a solution of the product from step 12 (195 mg, 0.366 mmol) in DMF (0.7 mmol) was added DIPEA (0.19 mL, 1.1 mmol) followed by HATU (195 mg, 0.51 mmol). Ammonium hydroxide (61 iL) was added after 5 min and stirring continued for 1 h. The reaction was quenched with NaHC03, extracted into EtOAc and the organic extracts washed with brine, dried (Na2S04), filtered, concentrated in vacuo and purified using MDAP to give the title compound Ή NMR (400 MHz, DMSO-J6) δ 7.48 - 7.26 (6H, m), 7.20 - 7.08 (3H, m), 6.62 (1H, s), 4.59 - 4.47 (2H, m), 4.36 (1H, d, J=17.7 Hz), 4.16 - 4.06 (1H, m), 3.17 (1H, d, J=4.1 Hz), 2.94 (1H, d, J=14.0 Hz), 2.77 (1H, d, J=13.4 Hz), 2.47 - 2.32 (1H, m), 2.14 - 2.07 (1H, m), 1.86 - 1.73 (1H, m), 1.70 - 1.62 (1H, m), 1.12 (3H, d, J=6.8 Hz); LCMS (ESI): m/z = 533 [M+H]+.
Example 8: Methyl 4-r2,5-difluoro-4-rr(3^',6i?)-3-methyl-lJ-dioxo-6-phenyl-thiazinan-2- yllmethyllphenylltetrahydropyran-4-carboxylate
Figure imgf000058_0001
A flask was charged with (35',6ii)-2-[(4-bromo-2-fluoro-phenyl)methyl]-3-methyl-6-phenyl- thiazinane 1 ,1-dioxide (10 g, 24 mmol), bis(dibenzylideneacetone)palladium (1.39 g, 2.4 mmol), 2-dicyclohexylphosphino-2',6'-di- -propoxy-l,l'-biphenyl (1.15 g, 2.4 mmol) and purged with nitrogen for 2 min. THF (120 mL), methyl tetrahydropyran-4-carboxylate (8.1 mL, 61 mmol) and zinc chloro 2,2,6,6-tetramethylpiperidide lithium chloride complex (93 mL, 0.65 M in THF) were subsequently added and the reaction was stirred at 60 °C for 2 h. The reaction was cooled to RT and quenched with a saturated aqueous solution of NH4C1 (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracted were dried with MgS04, filtered, concentrated and purified by silica gel column chromatography (0% to 100% EtOAc in heptane) to give the title compound (6.5 g, 56% yield). 1H NMR (400 MHz, DMSO-J6) δ 7.55 - 7.48 (m, 1H), 7.48 - 7.43 (m, 2H), 7.43 - 7.33 (m, 3H), 7.26 - 7.20 (m, 1H), 7.18 - 7.12 (m, 1H), 4.58 - 4.47 (m, 2H), 4.41 - 4.32 (m, 1H), 4.20 - 4.06 (m, 1H), 3.85 - 3.75 (m, 2H), 3.66 - 3.60 (s, 3H), 3.47 - 3.36 (m, 2H), 2.47 - 2.31 (m, 3H), 2.15 - 2.05 (m, 1H), 1.96 - 1.74 (m, 3H), 1.71 - 1.61 (m, 1H), 1.15 - 1.07 (d, / = 6.9 Hz, 3H).
Example 9: N-(Cyclopropylmethyl)-4-r3-fluoro-4-rr(3^',6i?)-3-methyl-l J-dioxo-6-phenyl-
Figure imgf000059_0001
Step 1 : 4-(3-Huoro-4-(((35.6R)-3-metfayl-l J-dioxido-6-phenyl-1.2-t azinan-2
yl)methyl)phenyl)tetrahydro-2H-pyran-4-carboxylic acid
To a solution of methyl 4-[3-fluoro-4-[[(3.S',6ii)-3-methyl-l ,l-dioxo-6-phenyl-thiazinan- 2-yl]methyl]phenyl]tetrahydropyran-4-carboxylate (5.67 g, 12 mmol) in THF (60 mL) and water (20 mL) was added lithium hydroxide hydrate (5.0 g, 119 mmol) and the reaction was stirred at RT for 72 h. The reaction was diluted with water (50 mL) and the pH was adjusted to 1 using 1 N aqueous HC1. The product was extracted with EtOAc (3 x 75 mL), dried over MgS04, concentrated, and purified by silica gel chromatography (0% to 100% EtOAc in heptane) to give the title compound (4.0 g, 73% yield). 1H NMR (400 MHz, DMSO-J6) δ 7.54 - 7.43 (m, 3H), 7.43 - 7.33 (m, 3H), 7.28 - 7.23 (m, 1H), 7.18 - 7.12 (m, 1H), 4.58 - 4.46 (m, 2H), 4.42 - 4.32 (m, 1H), 4.19 - 4.05 (m, 1H), 3.84 - 3.74 (m, 2H), 3.51 - 3.38 (m, 2H), 2.47 - 2.41 (m, 1H), 2.38 - 2.30 (m, 2H), 2.16 - 2.06 (m, 1H), 1.88 - 1.74 (m, 3H), 1.72 - 1.61 (m, 1H), 1.15 - 1.05 (d, J = 6.8 Hz, 3H).
Step 2: N-(Cvclopropylmethyl)-4-r3-fluoro-4-rr(3^',6i?)-3-methyl-lJ-dioxo-6-phenyl-thiazinan- 2-yllmethyllphenylltetrahydropyran-4-carboxamide A vial was charged with the product from step 1 (50 mg, 0.11 mmol),
cyclopropylmethylamine (23 mg, 0.33 mmol), DMF (14 mL), and triethylamine (0.045 mL, 0.33 mmol). To the solution was then added HATU (63 mg, 0.16 mmol) and the reaction was stirred at RT for 16 h. The reaction was partitioned between water and DCM, and the organic layer was separated using a phase-separation cartridge, concentrated, and purified by preparative HPLC to give the title compound (16 mg, 24% yield). 1H NMR (400 MHz, DMSO-J6) δ 7.72 (t, / = 5.8 Hz, 1H), 7.52 - 7.43 (m, 3H), 7.43 - 7.31 (m, 3H), 7.21 (dd, .7 = 8.3, 1.8 Hz, 1H), 7.12 (dd, J = 12.5, 1.8 Hz, 1H), 4.56 - 4.46 (m, 2H), 4.40 - 4.31 (m, 1H), 4.17 - 4.07 (m, 1H), 3.80 - 3.71 (m, 2H), 3.45 (t, / = 11.2 Hz, 2H), 2.94 (t, / = 6.2 Hz, 2H), 2.49 - 2.37 (m, 3H), 2.14 - 2.05 (m, 1H), 1.89 - 1.74 (m, 3H), 1.70 - 1.61 (m, 1H), 1.09 (d, / = 6.9 Hz, 3H), 0.92 - 0.81 (m, 1H), 0.34 - 0.24 (m, 2H), 0.10 - 0.03 (m, 2H).
Example 10: 1- r2,5-Difluoro-4- \\(3S,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yllmethyllphenyll-N-(isoxazol-4-ylmethyl)ethanamine
Figure imgf000060_0001
Step 1 : N-(l-(4-(((fer?-Butyldimethylsilyl)oxy)methyl)-2,5-difluorophenyl)ethyl)-2- methylpropane-2-sulfinamide
To a solution of ((4-bromo-2,5-difluorobenzyl)oxy)(ter/-butyl)dimethylsilane (10 g, 29.8 mmol) in diethyl ether (200 mL) at -78 °C was added dropwise n-butyllithium (2.5 M in hexanes, 14.2 mL, 35.6 mmol). The resulting mixture was stirred at -78 °C for 1 h, then a solution of (E)-N-ethylidene-2-methylpropane-2-sulfinamide (5.8 g, 39.4 mmol) in diethyl ether (30 mL) was added dropwise at -78 °C and the reaction mixture was stirred at -78 °C for 30 min. The reaction was quenched with saturated ammonium chloride solution (100 mL), extracted with EtOAc (2x100 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by Biotage Flash column (40 g silica, UV254, 0-30% PE/EA) to obtain the title product (10 g, 83% yield) as colorless oil. LCMS (ESI): m/z = 406.2 [M+H]+. Step 2: N-(l-(2,5-Difluoro-4-(hydroxymethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide To a solution of the product from step 1 (7.7 g, 19 mmol) in THF (100 mL) was added
TBAF (38 mL, 38 mmol) and the reaction mixture was stirred at 25 °C for 1 h. The solvent was removed and the residue was diluted with EtOAc (100 mL), then washed with water (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with 0-50% EtOAc in PE to afford (4.9 g, 76 % yield) as colorless oil. LCMS (ESI): m/z = 292.1 [M+H]+.
Step 3: N-(l-(4-(Chloromethyl)-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide
To a solution of the product from step 2 (4.9 g, 16.8 mmol) in DCM (100 mL) was added triethylamine (5.1 g, 50.5 mmol) and methanesulfonyl chloride (3.9 g, 33.6 mmol) at 0 °C. The reaction mixture was stirred at 25 °C overnight. The reaction was quenched with water (50 mL), extracted with DCM (2 x 50 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by Biotage Flash column (40 g silica, UV254, PE/EA=l :0-2:3) to give the title product (3.4 g, 65% yield) as a white solid. LCMS (ESI): m/z = 310.0 [M+H]+.
Step 4: N-(l-(2,5-Difluoro-4-(((3tS',6^)-3-methyl-l,l-dioxido-6-phenyl-l,2-thiazinan-2- yl)methyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide
To a solution of the product from step 3 (3.4 g, 11 mmol) in DMF (50 mL) was added (3S,6ii)-3-methyl-6-phenyl-thiazinane 1,1-dioxide (2.9 g, 13 mmol) and cesium carbonate (12.4 g, 38 mmol). The reaction was stirred at 25 °C for 16 h. The reaction was quenched with saturated NH4CI solution (100 mL), extracted with EtOAc (50 mL x 3), dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by
Biotage Flash column (40 g silica, UV254, 0-50% PE/EA) to give the title product (4.6 g, 84% yield) as light yellow oil. LCMS (ESI): m/z = 499.2 [M+H]+.
Step 5 : 1 -(2,5 -Difluoro-4-(((3^',6i?)-3-methyl- 1 , 1 -dioxido-6-phenyl- 1 ,2-thiazinan-2- yl)methyl)phenyl)ethan- 1 -aminium chloride
To a solution of the product from step 4 (4.6 g, 9.2 mmol) in MeOH (20 mL) was added dropwise HCl in 1,4-dioxane (4 M, 6.9 mL, 27.7 mmol) at 0 °C. The reaction was stirred at 0 °C for 30 min. The solvent was removed in vacuo and the crude product was triturated with diethyl ether, filtered, washed with more diethyl ether, dried under a high vacuum system for 1 h to give the title product (3.8 g, 96% yield) as a white solid. LCMS (ESI): m/z = 395.2 [M+H]+; lH NMR (400 MHz, DMSO-Je) δ 8.46 (s, 3H), 7.54-7.50 (m, IH), 7.47-7.46 (m, 2H), 7.40-7.31 (m, 4H), 4.61-4.52 (m, 3H), 4.43-4.37 (m, IH), 4.16-4.10 (m, IH), 2.47-2.44 (m, IH), 2.13-2.08 (m, IH), 1.82-1.79 (m, IH), 1.69-1.66(m, IH), 1.52-1.50(m, 3H),1.15-l.l l(m, 3H).
Step 6: l-r2,5-Difluoro-4-rr(3£,6i?)-3-methyl-l J-dioxo-6-phenyl-thiazinan-2-yllmethyllphenyll- N-(isoxazol-4-ylmethyl)ethanamine
To a solution of the product from step 5 (60 mg, 0.15 mmol) in MeOH (2 mL) was added isoxazole-4-carbaldehyde (22 mg, 0.23 mmol), acetic acid (0.02 mL), and sodium
cyanoborohydride (29 mg, 0.46 mmol). The reaction was stirred at 25 °C for 1 h then quenched with water (5 mL), extracted with EtOAc (2x10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC eluting with 25-55% CH3CN/H20 (0.1 % NH4HC03 in H20) to afford the title product (27 mg, 38% yield) as a white solid. LCMS (ESI): m/z = 476.1 [M+H]+; 1H NMR (400 MHz, DMSO-J6) δ 8.80 (d, J = 1.2 Hz, IH), 7.47-7.46 (m, 2H), 7.42-7.33 (m, 4H), 7.21-7.16 (m, IH), 6.57-6.56 (m, IH), 4.58-4.49 (m, 2H), 4.38-4.34 (m, IH), 4.15-4.10 (m, IH), 3.98-3.96 (m, IH), 3.66-3.54 (m, 2H), 2.88-2.86 (m, IH), 2.47-2.40 (m, IH), 2.12-2.08 (m, IH), 1.86-1.75 (m, IH), 1.69-1.65 (m, IH), 1.26-1.24 (m, 3H), 1.13-1.11 (m, 3H).
Example 11 : N-ri-r2,5-Difluoro-4-rr(3tS',6^)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yllmethyllphenyllethyll-2-isoxazol-4-yl-acetamide
Figure imgf000062_0001
To a solution of 2-(isoxazol-4-yl)acetic acid (38 mg, 0.3 mmol) in DMF (3 mL) was added HOBT (62 mg, 0.46 mmol), EDCI (87 mg, 0.46 mmol) and DIPEA (98 mg, 0.76 mmol). The reaction mixture was stirred at 25 °C for 5 min, then added (35',6ii)-2-(4-(l-aminoethyl)-2,5- difluorobenzyl)-3-methyl-6-phenyl-l,2-thiazinane 1,1-dioxide (60 mg, 0.15 mmol). The mixture was stirred at 25 °C overnight. The reaction was diluted with EtOAc (30 mL), washed with saturated aqueous NH4C1 (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC eluting with 25-55% CH3CN/H2O (0.1% NH4HCO3 in H20) to afford the title product (50 mg, 65% yield) as a white solid. LCMS (ESI): m/z = 504.0 [M+H]+; XH NMR (400 MHz, DMSO-J6) δ 8.81(s, IH), 8.75- 8.72 (m, IH), 7.47-7.45(m, 2H), 7.41-7.35(m, 3H), 7.23-7.16(m, 2H), 6.47(s, IH), 5.11-5.04(m, IH), 4.58- 4.47(m, 2H), 4.37-4.33(m, IH), 4.13-4.1 l(m, IH), 3.63(d, J = 4Hz, 2H), 2.47-2.39(m, IH), 2.12-2.08(m, IH), 1.84-1.75(m, IH), 1.68-1.64(m, IH), 1.35(d, J = 6.8 Hz, 3H), l .l l(d, J = 6.8 Hz, 3H).
Example 12: (3^,6i?)-2-(2,5-Difluoro-4-(2-hydroxy-l-phenylethyl)benzyl)-3-methyl-6-phenyl- 1 ,2-thiazinane -dioxide
Figure imgf000063_0001
Step 1 : tert-Butyl 2-diazo-2-(2,5-difluoro-4-(((3tS',6i?)-3-methyl-l,l-dioxido-6-phenyl-l,2- thiazinan-2-yl)methyl)phenyl)acetate
To a solution of tert-buty\ 2-[2,5-difluoro-4-[[(3S,6ii)-3-methyl-l,l-dioxo-6-phenyl- thiazinan-2-yl]methyl]phenyl] acetate (3.0 g, 6.4 mmol) and 4-acetamidobenzenesulfonyl azide (1.9 g, 7.7 mmol) in acetonitrile (32 mL) at 0 °C was added l ,8-diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.0 mmol) and the reaction was stirred at 0 °C to RT over 16 h. The reaction was quenched with water, extracted with Et20, washed with 10% aqueous NaHC03, dried over MgS04, filtered, concentrated, and purified by silica gel column chromatography to give the title compound (2.3 g, 73% yield). LCMS (ESI): m/z = 514.4 [M+Na]+.
Step 2: fer/-Butyl 2-(2,5-difluoro-4-(((3^',6i?)-3-methyl-l J-dioxido-6-phenyl-l,2-thiazinan-2- yl)methyl)phenyl)-2-phenylacetate
A vial was charged with the product of step 1 (500 mg, 1.01 mmol), phenylboronic acid (372 mg, 3.05 mmol) and bis((l ,5-cyclooctadiene)(hydroxo)rhodium) (24 mg, 0.051 mmol) and purged with nitrogen. 1 ,4-Dioxane (5 mL) and water (0.25 mL) were added and the reaction was stirred at 40 °C for 16 h. The reaction was concentrated on silica gel and purified by silica gel column chromatography to give the title compound (490 mg, 89% yield). LCMS (ESI): m/z = 542 [M+H]+.
Step 3: (3^,6i?)-2-(2,5-Difluoro-4-(2-hydroxy-l-phenylethyl)benzyl)-3-methyl-6-pheny thiazinane 1,1 -dioxide
To a solution of the product of step 2 (490 mg, 0.90 mmol) in THF (5 mL) at 0 °C was added lithium aluminum hydride (1.4 mL, 2.0 M in THF) and the reaction was stirred at 0 °C for 1 h. The reaction was quenched with 50% aqueous potassium sodium tartrate, extracted with Et20, dried over MgS04, filtered, and purified by silica gel column chromatography to give the title compound (213 mg, 50% yield). 1H NMR (400 MHz, DMSO-J6) δ 7.48 - 7.42 (m, 2H), 7.42 - 7.13 (m, 10H), 4.93 (t, / = 5.2 Hz, 1H), 4.58 - 4.43 (m, 2H), 4.39 - 4.27 (m, 2H), 4.19 - 4.06 (m, 1H), 4.05 - 3.95 (m, 1H), 3.95 - 3.86 (m, 1H), 2.47 - 2.36 (m, 1H), 2.16 - 2.03 (m, 1H), 1.88 - 1.73 (m, 1H), 1.72 - 1.61 (m, 1H), 1.11 (d, J = 6.8 Hz, 3H).
The above compounds, together with additional compounds made using the above procedures, are shown in Table 4 below, together with IC50 values for RORc.
Table 4
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
yl] methyl]phenyl] acetamide
Figure imgf000067_0001
Figure imgf000068_0001
-4-carboxamide
Figure imgf000069_0001
Figure imgf000070_0001
(isoxazol-4-ylmethyl)ethanamine
Figure imgf000071_0001
yl]methyl]phenyl]ethyl]-lH- imidazole-4-carboxamide
N-[l-[2,5-difluoro-4-[[(3S,6R)-3- methyl- 1 , 1 -dioxo-6-phenyl- thiazinan-2- yl] methyl]phenyl]ethyl] -3 - methyl-isoxazole-4-carboxamide
N-[l-[2,5-difluoro-4-[[(3S,6R)-3- methyl- 1 , 1 -dioxo-6-phenyl- thiazinan-2- yl]methyl]phenyl]ethyl]-l- methyl-pyrazole-4-carboxamide
N-[l-[2,5-difluoro-4-[[(3S,6R)-3- methyl- 1 , 1 -dioxo-6-phenyl- thiazinan-2- yl]methyl]phenyl]ethyl]-l- methyl-imidazole-4-carboxamide
N-[l-[2,5-difluoro-4-[[(3S,6R)-3- methyl- 1 , 1 -dioxo-6-phenyl- thiazinan-2- yl]methyl]phenyl]ethyl]pyrimidin e-5-carboxamide
N-[l-[2,5-difluoro-4-[[(3S,6R)-3- methyl- 1 , 1 -dioxo-6-phenyl- thiazinan-2- yl]methyl]phenyl]ethyl]-4- methyl-oxazole-5-carboxamide
N-[l-[2,5-difluoro-4-[[(3S,6R)-3- methyl- 1 , 1 -dioxo-6-phenyl- thiazinan-2- yl]methyl]phenyl]ethyl]oxazole- 4-carboxamide
N-[l-[2,5-difluoro-4-[[(3S,6R)-3- methyl- 1 , 1 -dioxo-6-phenyl- thiazinan-2- yl]methyl]phenyl]ethyl]pyrimidin e-4-carboxamide
N-[l-[2,5-difluoro-4-[[(3S,6R)-3- methyl- 1 , 1 -dioxo-6-phenyl- thiazinan-2- yl] methyl]phenyl]ethyl] -3 - methyl-isoxazole-5-carboxamide
N-[l-[2,5-difluoro-4-[[(3S,6R)-3 methyl- 1 , 1 -dioxo-6-phenyl- thiazinan-2- yl]methyl]phenyl]ethyl]-lH-
Figure imgf000072_0001
pyrazole-3-carboxamide
Figure imgf000073_0001
4-carboxamide
N-[l-[2,5-difluoro-4-[[(3S,6R)-3- methyl- 1 , 1 -dioxo-6-phenyl-
79 thiazinan-2- 0.0030 yl]methyl]phenyl]ethyl]thiadiazol
0 1 F e-4-carboxamide
Table 4
Proton NMR data for selected compounds of Table 4 are shown below, with the compound numbers corresponding to the numbering in Table 4.
Compound 4: Ή NMR (400 MHz, DMSO-J6) δ 7.54 - 7.50 (IH, m), 7.45 - 7.33 (6H, m), 7.27 - 7.14 (2H, m), 6.99 (IH, s), 4.56 - 4.43 (4H, m), 4.36 - 4.22 (2H, m), 4.13 - 4.07 (2H, m), 2.86 - 2.76 (IH, m), 2.45 - 2.35 (IH, m), 2.26 - 2.16 (IH, m), 2.11 - 2.03 (IH, m), 1.97 - 1.88 (IH, m), 1.84 - 1.71 (IH, m), 1.67 - 1.60 (IH, m), 1.08 (3H, d, J=6.9 Hz).
Compound 5 : Ή NMR (400 MHz, DMSO-J6) δ 7.54 - 7.50 (IH, m), 7.45 - 7.33 (6H, m), 7.27 - 7.14 (2H, m), 6.99 (IH, s), 4.56 - 4.43 (4H, m), 4.36 - 4.22 (2H, m), 4.13 - 4.07 (2H, m), 2.86 - 2.76 (IH, m), 2.45 - 2.35 (IH, m), 2.26 - 2.16 (IH, m), 2.11 - 2.03 (IH, m), 1.97 - 1.88 (IH, m), 1.84 - 1.71 (IH, m), 1.67 - 1.60 (IH, m), 1.08 (3H, d, J=6.9 Hz).
Compound 8: Ή NMR (400 MHz, DMSO-J6) δ 7.63 (IH, s), 7.48 - 7.33 (6H, m), 7.25 - 7.18 (2H, m), 4.89 - 4.88 (IH, m), 4.64 - 4.46 (6H, m), 4.38 - 4.26 (2H, m), 4.13 - 4.04 (IH, m), 2.42 - 2.40 (IH, m), 2.1 1 - 2.04 (IH, m), 1.84 - 1.71 (IH, m), 1.64 (IH, dd, J=2.1 , 14.2 Hz), 1.09 (3H, d, J=6.8 Hz).
Compound 9,: Ή NMR (400 MHz, DMSO-J6) δ 7.66 - 7.62 (IH, m), 7.48 - 7.33 (6H, m), 7.25 - 7.18 (2H, m), 4.89 (IH, s), 4.64 - 4.45 (6H, m), 4.38 - 4.26 (2H, m), 4.14 - 4.04 (IH, m), 2.45 - 2.35 (IH, m), 2.11 - 2.04 (IH, m), 1.84 - 1.60 (2H, m), 1.08 (3H, d, J=6.9 Hz.
Compound 29: lH NMR(400 MHz, DMSO-J6) δ 7.47-7.26 (m, 7H), 7.21 -7.17 (m, IH), 7.05-7.03 (m, IH), 4.59-4.48 (m, 2H), 4.38-4.34 (m, IH), 4.16-4.10 (m, IH), 3.98-3.92(m, IH), 2.98-2.80 (m, 2H), 2.67-2.55 (m, IH), 2.47-2.32 (m, IH), 2.13-2.07 (m, IH), 1.86-1.64 (m, 2H), 1.25 (d, / = 6 Hz, 3H), 1.12(d, / = 6.4 Hz, 3H).
Compound 34: XH NMR (400 MHz, DMSO-J6) δ 7.69 (d, / = 6.6 Hz, IH), 7.53 - 7.43 (m, 3H), 7.43 - 7.33 (m, 3H), 7.18 (d, / = 8.3 Hz, IH), 7.09 (d, / = 12.4 Hz, IH), 4.57 - 4.46 (m, 2H), 4.36 (d, / = 17.5 Hz, IH), 4.21 - 4.08 (m, 2H), 3.82 - 3.59 (m, 3H), 3.47 - 3.36 (m, 2H), 2.46 - 2.36 (m, 4H), 2.16 - 1.96 (m, 3H), 1.88 - 1.74 (m, 3H), 1.74 - 1.62 (m, 2H), 1.09 (d, / = 4.0 Hz, 3H). Compound 35: XH NMR (400 MHz, DMSO-J6) δ 7.90 (s, IH), 7.51 - 7.42 (m, 3H), 7.42 - 7.32 (m, 3H), 7.17 (dd, / = 8.3, 1.9 Hz, IH), 7.09 (dd, / = 12.4, 1.9 Hz, IH), 4.59 - 4.46 (m, 3H), 4.35 (d, / = 17.5 Hz, IH), 4.18 - 4.06 (m, IH), 3.78 - 3.68 (m, 2H), 3.49 - 3.36 (m, 4H), 2.46 - 2.35 (m, 3H), 2.15 - 2.04 (m, IH), 1.87 - 1.71 (m, 3H), 1.70 - 1.60 (m, IH), 1.08 (d, / = 6.9 Hz, 3H), 0.69 - 0.62 (m, 2H), 0.47 - 0.40 (m, 2H).
Compound 37: XH NMR (400 MHz, DMSO-J6) δ 7.57 (d, J = 6.5 Hz, IH), 7.49 - 7.43 (m, 2H), 7.43 - 7.34 (m, 3H), 7.23 - 7.13 (m, 2H), 4.91 (d, J = 5.4 Hz, IH), 4.59 - 4.47 (m, 2H), 4.37 (d, J = 17.7 Hz, IH), 4.23 - 4.06 (m, 3H), 3.71 - 3.62 (m, 2H), 3.62 - 3.52 (m, 2H), 2.47 - 2.37 (m, IH), 2.36 - 2.27 (m, 2H), 2.15 - 1.96 (m, 5H), 1.96 - 1.86 (m, 2H), 1.86 - 1.75 (m, IH), 1.73 - 1.62 (m, IH), 1.11 (d, J = 6.9 Hz, 3H).
Compound 38: XH NMR (400 MHz, DMSO-J6) δ 7.57 (d, / = 7.0 Hz, IH), 7.50 - 7.43 (m, 2H), 7.43 - 7.34 (m, 3H), 7.22 - 7.12 (m, 2H), 4.98 (d, / = 5.5 Hz, IH), 4.61 - 4.47 (m, 2H), 4.37 (d, / = 17.8 Hz, IH), 4.18 - 4.06 (m, IH), 3.80 - 3.70 (m, IH), 3.70 - 3.61 (m, 3H), 3.60 - 3.52 (m, 2H), 2.44 - 2.35 (m, 3H), 2.35 - 2.27 (m, 2H), 2.14 - 2.06 (m, IH), 1.99 - 1.84 (m, 2H), 1.84 - 1.75 (m, IH), 1.75 - 1.62 (m, 3H), 1.12 (d, / = 6.8 Hz, 3H).
Compound 39: Ή NMR (400 MHz, DMSO-J6) δ 8.60 - 8.59 (2H, m), 7.46 - 7.34 (6H, m), 7.15 (IH, dd, J=7.0, 13.3 Hz), 6.96 - 6.89 (IH, m), 4.75 - 4.61 (IH, m), 4.52 - 4.38 (2H, m), 4.28 (IH, d, J=17.3 Hz), 4.11 - 4.04 (IH, m), 3.81 - 3.72 (IH, m), 3.56 (IH, d, J=13.0 Hz), 3.18 - 3.1 1 (IH, m), 2.92 (IH, dd, J=10.7, 12.5 Hz), 2.45 - 2.35 (2H, m), 2.11 - 1.95 (2H, m), 1.84 - 1.71 (IH, m), 1.63 (IH, dd, J=2.3, 14.1 Hz), 1.08 (3H, d, J=6.9 Hz).
Compound 40: Ή NMR (400 MHz, DMSO-J6) δ 8.60 - 8.59 (2H, m), 7.46 - 7.34 (6H, m), 7.15 (IH, dd, J=7.0, 13.3 Hz), 6.96 - 6.89 (IH, m), 4.75 - 4.61 (IH, m), 4.52 - 4.38 (2H, m), 4.28 (IH, d, J=17.3 Hz), 4.11 - 4.04 (IH, m), 3.81 - 3.72 (IH, m), 3.56 (IH, d, J=13.0 Hz), 3.18 - 3.1 1 (IH, m), 2.92 (IH, dd, J=10.7, 12.5 Hz), 2.45 - 2.35 (2H, m), 2.11 - 1.95 (2H, m), 1.84 - 1.71 (IH, m), 1.63 (IH, dd, J=2.3, 14.1 Hz), 1.08 (3H, d, J=6.9 Hz).
Compound 53 : Ή NMR (400 MHz, DMSO-J6) δ 7.48 - 7.26 (6H, m), 7.20 - 7.08 (3H, m), 6.62 (IH, s), 4.59 - 4.47 (2H, m), 4.36 (IH, d, J=17.7 Hz), 4.16 - 4.06 (IH, m), 3.17 (IH, d, J=4.1 Hz), 2.94 (IH, d, J=14.0 Hz), 2.77 (IH, d, J= 13.4 Hz), 2.47 - 2.32 (IH, m), 2.14 - 2.07 (IH, m), 1.86 - 1.73 (IH, m), 1.70 - 1.62 (IH, m), 1.12 (3H, d, J=6.8 Hz).
Example 13 In vitro RQRc Ligand Binding Assay This assay was used to determine a compound's potency in inhibiting activity of RORc by determining, Kiapp, IC50, or percent inhibition values. Consumables used in this Example are shown in Table 5 below.
Table 5
Figure imgf000076_0001
Table 5
Filter Plate Preparation
On day of the assay, 100 uL of 0.05% CHAPS (in deionized H20) was added to all wells of the GFB Unifilter plate and allowed soak for 1 h. A wash buffer of 50 mM HEPES (pH 7.4), 150 mM NaCl, and 5 mM MgCl2 was prepared to wash the filter plate. To prepare an assay buffer, BSA was added to the wash buffer to reach 0.01% and DTT was added to reach 1 mM.
Compounds
For IC50 mode, 10 mM compound stocks were serially diluted in DMSO with DMSO to give 20x required final concentration in DMSO (15 uL compound + 30 uL DMSO). The 20x compound stocks were diluted in DMSO with Assay Buffer 4-fold to reach 5x the final test concentration in 25% DMSO (10 uL compound + 30 uL Assay Buffer). Solutions were mixed by aspiration several times with a pipette set on 50 uL volume. For the assay, 10 uL of 5x compound stock solutions in 25% DMSO were added to the assay plate in duplicate.
For two point screening, 10 mM stock compound solutions were diluted in DMSO to obtain 200 uM (20x the high test concentration) and then diluted 10-fold further to reach 20 uM (20x the low test concentration). The 20x stocks were diluted 4-fold with Assay Buffer (10 uL compound + 30 uL Assay Buffer) to reach 5x the test concentrations (50 uM and 5 uM) and 10 uL were added to two assay plates for the duplicate wells. With each concentration tested on 2 plates, each set of 80 compounds used 4 assay plates (1 uM and 10 uM, with n=2).
Nonspecific binding (NSB) samples, Total Binding (TB) samples and No Receptor (No R) samples
25-hydroxycholesterol (1 uM) was used to determine the level of NSB signal is prepared in
DMSO as for compounds above, then diluted in Assay Buffer to give a final concentration of 5 uM. For 25-hydroxycholesterol in 25% DMSO/75% Assay Buffer; 10 uL per well was used for NSB samples. Wells for Total Binding and No Receptor sample determination contained 10 uL of 25% DMSO/75% Assay Buffer per well.
Radioligand (25-[3Hlhydroxycholesterol) Preparation
25-[3H]hydroxycholesterol was diluted in Assay Buffer to obtain 15 nM and vortex to mix. Add 20 uL to all wells to reach 6 nM final concentration in the assay.
Receptor Preparation
The optimal concentration for RORc receptor was found to be 0.6 ug/mL. Stock receptor solution was diluted in assay buffer to obtain 1.5 ug/mL in Assay Buffer. 20 uL was added to all wells.
For No Receptor samples, 20 uL Assay Buffer was substituted for receptor solution.
Sample addition to Plates and Incubation
Assay plates were 96-well polypropylene V-bottom plates. 10 uL of 5x compound in
25% DMSO/75% Assay Buffer was added to Test wells. 10 uL of 25% DMSO/75% Assay Buffer was added to Total Binding or No Receptor wells. 10 uL of 5 uM 25-hydroxycholesterol in 25% DMSO/75%
Assay Buffer was added to NSB wells. 20 uL of 15 nM 25-[3H]hydroxycholesterol prepared in Assay
Buffer was added to all wells. 20 uL of 1.5 ug/mL RORc receptor was added to wells (or 40 uL Assay
Buffer to No R wells). Following addition to the wells, the plates were incubated 3 h at 25°C.
Filtration
Using a Packard Filtermate Harvester, the filter plate were washed 4 times following transfer of the incubated samples. Plates were dry-filtered completely (2 h at 50 °C or overnight at room temperature). 50 uL Microscint 0 was added to all wells and read on Topcount protocol Inverted.
Final concentrations
Final concentrations were as follows: 50 mM HEPES buffer (pH 7.4); 150 niM NaCl; 1 niM DTT; 5 mM MgCl¾ 0.01% BSA; 5% DMSO; 0.6 ug/mL RORc receptor; 6 nM 25-
[3H]hydroxycholesterol. For NSB wells, 1 uM 25-hydroxycholesterol was also present.
Example 14: RORc Coactivator Peptide Binding Assay
Assays were carried out in 16-microL reaction volumes in black 384 Plus F Proxiplates (Perkin- Elmer 6008269). All assay components except test ligand were mixed in coregulator buffer D (Invitrogen PV4420) containing 5 niM DTT and added to the plate at twice their final concentrations in a volume of 8 microL. Test ligands at 2x the final concentration were then added to the wells in 8 L of coregulator buffer D containing 5 niM DTT and 4% DMSO. Final incubations contained lx coregulator buffer D, 5 niM DTT, test ligand, 2% DMSO, 50 nM biotinyl-CPSSHSSLTERKHKILHRLLQEGSPS (American Peptide Company; Vista, CA), 2 nM Europium anti-GST (Cisbio 61GSTKLB), 12.5 nM streptavidin-D2 (Cisbio 610SADAB), 50 mM KF, and 10 nM of bacterially-expressed human RORc ligand binding domain protein containing an ^-terminal 6xHis-GST-tag and residues 262-507 of Accession NP_005051. Ten test ligand concentrations were tested in duplicate. After the reaction plates were incubated for 3 h in the dark at room temperature (22-23 °C), the plate was read on an EnVision plate reader (PerkinElmer) following the Europium/D2 HTRF protocol (ex 320, em 615 and 665, 100 s lag time, 100 flashes, 500 μ8 window). The time-resolved FRET signal at 665 nm was divided by that at 615 nm to generate the signal ratio of each well. The signal ratio of wells containing RORc and peptide but no test ligand were averaged and set to 0% Effect while the signal ratios of the blank wells containing coactivator peptide but no RORc were averaged and set to -100% Effect. RORc exhibits a basal (constitutive) signal in this assay and test ligands can increase or decrease the signal ratio relative to this basal signal level. RORc agonists increase the signal ratio in this assay and result in a positive % Effect value. Inverse agonists decrease the signal ratio, and result in a negative % Effect value. The EC50 value is the concentration of test compound that provides half-maximal effect (increased or decreased assay signal) and is calculated by Genedata Screener® software (Genedata; Basel, Switzerland) using the following equation:
% Effect = So + {(SM - S0)/[l+(10logEC5o/10c)n] }
where S0 equals the activity level at zero concentration of test compound, Sinf is the activity level at infinite concentration of test compound, EC50 is the concentration at which the activity reaches 50% of the maximal effect, c is the concentration in logarithmic units corresponding to the values on the x-axis of the dose-response curve plot, and n is the Hill coefficient (the slope of the curve at the EC50).
Example 15: Arthritis Mouse Model
8 to 10-week old male DBA/1 (DBA/lOlaHsd, Harlan Laboratories) mice are housed in a specific pathogen free (SPF) animal facility. Arthritis is induced by two injections of collagen subcutaneously in the base of the tail. The initial injection (on day 0) uses bovine type II collagen (2 mg/ml from Chondrex, Redmond, Wash.) emulsified in equal volume of CFA containing 4 mg/ml of M. tuberculosis (Chondrex). The CII booster injection on Day 29 is emulsified in incomplete Freund's adjuvant (IF A). Each animal receives 0.1 ml of emulsion by subcutaneous/intradermal injection in the tail 2 to 3 cm from the body of the mouse. The booster injection site is in the vicinity of but different from the initial injection site and closer to the body of the animal. OR- 1050 was formulated in HRC-6 as above. On weekdays, the animals receive two doses (a.m. and p.m.) of HRC-6 or 50 mg kg OR-1050 p.o. (2.5 mls kg). On weekends, a single dose of 100 mg kg is administered (5 mls/kg).
The mice are observed daily for clinical symptoms of CIA based on the following qualitative scale. Each paw was examined individually and scored. Grade 0, normal; grade 1, mild but definite redness and swelling of the ankle or wrist, or apparent redness and swelling limited to individual digits, regardless of the number of affected digits; grade 2, moderate redness and swelling of ankle or wrist; grade 3, severe redness and swelling of the entire paw including digits; grade 4, maximally inflamed limb with involvement of multiple joints. To estimate cumulative disease severity for each animal, an area under the curve score is calculated for each animal by totaling the sum of the daily hind paw measurements betweens days 24 and 48.
Example 16: Muscular Sclerosis Mouse Model I
Experiments are conducted on female mice aged 4-6 weeks belong to the C57BL/6 strain weighing 17-20 g. Experimental autoimmune encephalomyelitis (EAE) is actively induced using 95% pure synthetic myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35.55) (Invitrogen). Each mouse is anesthetized and receives 200 ug of MOG35.55 peptide and 15 ug of Saponin extract from Quilija bark emulsified in 100 uL of phosphate-buffered saline. A 25 uL volume is injected subcutaneously over four flank areas. Mice are also intraperitoneally injected with 200 ng of pertussis toxin in 200 uL of PBS. A second, identical injection of pertussis toxin is given after 48 h.
A compound of the invention is administered at selected doses. Control animals receive 25 uL of DMSO. Daily treatment extends from day 26 to day 36 post-immunization. Clinical scores are obtained daily from day 0 post-immunization until day 60. Clinical signs are scored using the following protocol: 0, no detectable signs; 0.5, distal tail limpness, hunched appearance and quiet demeanor; 1, completely limp tail; 1.5, limp tail and hindlimb weakness (unsteady gait and poor grip with hind limbs); 2, unilateral partial hind limb paralysis; 2.5, bilateral hind limb paralysis; 3, complete bilateral hindlimb paralysis; 3.5, complete hindlimb paralysis and unilateral forelimb paralysis; 4, total paralysis of hind limbs and forelimbs (Eugster et al., Eur J Immunol 2001, 31, 2302-2312).
Inflammation and demyelination may be assessed by histology on sections from the CNS of EAE mice. Mice are sacrificed after 30 or 60 days and whole spinal cords are removed and placed in 0.32 M sucrose solution at 4° C. overnight. Tissues are prepared and sectioned. Luxol fast blue stain is used to observe areas of demyelination. Haematoxylin and eosin staining is used to highlight areas of inflammation by darkly staining the nuclei of mononuclear cells. Immune cells stained with H&E are counted in a blinded manner under a light microscope. Sections are separated into gray and white matter and each sector is counted manually before being combined to give a total for the section. T cells are immunolabeled with anti-CD3+ monoclonal antibody. After washing, sections are incubated with goat anti-rat HRP secondary antibody. Sections are then washed and counterstained with methyl green.
Splenocytes isolated from mice at 30 and 60 days post-immunization are treated with lysis buffer to remove red blood cells. Cells are then re-suspended in PBS and counted. Cells at a density of about 3xl06 cells/mL are incubated overnight with 20 ug/mL of MOG peptide. Supernatants from stimulated cells are assayed for IFNgamma protein levels using an appropriate mouse IFN-gamma immunoassay system. Example 17: Muscular Sclerosis Mouse Model II
In this model, female rodents are anesthetized with isoflurane and injected with Freund's Incomplete Adjuvant containing 1 mg/niL neuronal antigen (e.g. myelin basic protein, myelin oligodendrocyte glycoprotein, proteolipid protein) and 4 mg/niL mycobacterium tuberculosis at two sites on the back on day 0 of this study. A compound of interest is then dosed daily in a sub-cutaneous, intra- peritoneally, or oral manner from day 0 until the end of study at an efficacious dose. Daily observations of degree of paralysis are taken as measures of efficacy.
Example 18: Psoriasis Mouse Model I
The severe, combined immunodeficient (SCID) mouse model can be used to evaluate the efficacy of compounds for treating psoriasis in humans (Boehncke, Ernst Schering Res Found Workshop 2005, 50, 213-34; and Bhagavathula et al., J Pharmacol Expt'l Therapeutics 2008, 324(3), 938-947). Briefly, SCID mice are used as tissue recipients. One biopsy for each normal or psoriatic volunteer (human) is transplanted onto the dorsal surface of a recipient mouse. Treatment is initiated 1 to 2 weeks after transplantation. Animals with the human skin transplants are divided into treatment groups. Animals are treated twice daily for 14 days. At the end of treatment, animals are photographed and then euthanized. The transplanted human tissue along with the surrounding mouse skin is surgically removed and fixed in 10% formalin and samples obtained for microscopy. Epidermal thickness is measured. Tissue sections are stained with an antibody to the proliferation-associated antigen Ki-67 and with an anti-human CD3.sup.+ monoclonal antibody to detect human T lymphocytes in the transplanted tissue. Sections are also probed with antibodies to c-myc and beta-catenin. A positive response to treatment is reflected by a reduction in the average epiderma thickness of the psoriatic skin transplants. A positive response is also associated with reduced expression of Ki-67 in keratinocytes.
Example 19: Psoriasis Mouse Model II
Using the Imidquimod model of skin inflammation (Fits et al, Journal of Immunology, 2009, 182: 5836-5845), 10-12 week old BALB/c, I117c+/+ or 1117c-/-, or I117re+/+ or I117re-/- mice were administered 50 mg Aldara cream (5% Imidquimod in Graceway, 3M) in the shaved back and right ear daily for 5 days. Clinical scoring and ear thickness measurements were performed daily. Scoring was based upon the manifestation of psoriatic symptoms, such as erythema, scaling and thickness: 0, No disease. 1, Very mild erythema with very mild thickening and scaling involving a small area. 2, Mild erythema with mild thickening and scaling involving a small area. 3, Moderate erythema with moderate thickening and scaling (irregular and patchy) involving a small area (<25%). 4, Severe erythema with marked thickening and scaling (irregular and patchy) involving a moderate area (25-50%). 5, Severe erythema with marked thickening and scaling (irregular and patchy) involving a large area (>50%). Ear and back tissue were harvested on day 5 for histological evaluation. Efficacy of compounds is compared in the imiquimod (IMQ) mouse model of psoriasis. Balb/c mice (10 males/group) received daily topical IMQ (5% cream) on shaved back and right ear for 5 days as described above. Animals received oral dose of a representative compound or DMF (45 or 90 mg-eq MMF/kg twice daily) or vehicle from Day -5 to Day +5. Erythema score is the primary outcome measure. The Erythema score values of the compounds tested at an oral dose of 90 mg-eq MMF/kg BID for 10 days in male Balb/C mice are set forth in Table 3, below. The data shows that the compounds of the disclosure are equipotent to DMF.
Example 20: Irritable Bowel Disease Mouse Model I
Effectiveness in treatment of inflammatory bowel disease may be evaluated as described by Jurjus et al., J Pharmaocol Toxicol Methods 2004, 50, 81-92; Villegas et al., Int'l Immunopharmacol 2003, 3, 1731-1741 ; and Murakami et al., Biochemical Pharmacol 2003, 66, 1253-1261. Briefly, female ICR mice are divided into treatment groups which are given either water (control), 5% DSS in tap water is given at the beginning of the experiment to induce colitis, or various concentrations of test compound. After administering test compound for 1 week, 5% DSS in tap water is also administered to the groups receiving test compound for 1 week. At the end of the experiment, all mice are sacrificed and the large intestine is removed. Colonic mucosa samples are obtained and homogenized. Proinflammatory mediators (e.g., IL-lalpha, IL-lbeta, TNFalpha, PGE2, and PGF2alpha.) and protein concentrations are quantified. Each excised large intestine is histologically examined and the damage to the colon scored.
Example 21: Chronic Obstructive Pulmonary Disease Mouse Model
The cigarette smoke model of Martorana et al., Am J Respir Crit Care Med 2005, 172, 848-835; and Cavarra et al., Am J Respir Crit Care Med 2001, 164, 886-890 can be used for assessing efficacy in treating emphysema. Briefly, six-week old C57B 1/6J male mice are exposed either to room air or to the smoke of five cigarettes for 20 minutes. For the acute study, mice are divided into three groups of 40 animals each. These groups are then divided into four subgroups of 10 mice each as follows: (1) no treatment/air-exposed; (2) no treatment/smoke-exposed; (3) a first dose of test compound plus smoke- exposed; and (4) a second dose of test compound. In the first group, trolox equivalent antioxidant capacity is assessed at the end of the exposure in bronchoalveolar lavage fluid. In the second group, cytokines and chemokines are determined in bronchoalveolar lavage fluid using a commercial cytokine panel at 4 hours; and in the third group bronchoalveolar lavage fluid cell count is assessed at 24 hours. In a chronic study, the mice are exposed to either room air or to the smoke of three cigarettes/day, for 5 days/week, for 7 months. Five groups of animals are used: (1) no treatment/air- exposed; (2) a first dose of a test compound plus air-exposed; (3) no treatment/smoke-exposed; (4) a second dose of the test compound plus smoke-exposed; and (5) the first dose of the test compound plus smoke exposed. Seven months after chronic exposure to room air or cigarette smoke, 5 to 12 animals from each group are sacrificed and the lungs fixed intratracheally with formalin. Lung volume is measured by water displacement. Lungs are stained. Assessment of emphysema includes mean linear intercept and internal surface area. The volume density of macrophages, marked immunohistochemically with anti-mouse Mac-3 monoclonal antibodies is determined by point counting. A mouse is considered to have goblet cell metaplasia when at least one or more midsize bronchi/lung showed a positive periodic acid-Schiff staining for the determination of desmosine, fresh lungs are homogenized, processed, and analyzed by high-pressure liquid chromatography.
Example 22: Asthma Mouse Model
A single inhaled allergen challenge can induce an acute increase in airway responsiveness in some individuals and animal models. However, repeated allergen inhalations have demonstrated more pronounced, consistent, and prolonged increases in airway responsiveness. This mouse model of long- term repeated inhalations of allergen has been used to study the long term effect of allergic diseases in the lung, and to delineate the cells, mechanisms, molecules, and mediators involved in the induction of airway hyperresponsiveness of lung in humans.
Crystalline OVA is obtained from Pierce Chem. Co. (Rockford, 111.) aluminum potassium sulfate (alum) from Sigma Chem. Co. (St. Louis, Mo.), pyrogen-free distilled water from Baxter, Healthcare Corporation (Deerfield, 111.), 0.9% sodium chloride (normal saline) from Lymphomed (Deerfield, 111.) and Trappsol.TM. HPB-L100 (aqueous hydroxypropylbeta cyclodextrin; 45 wt/vol % aqueous solution) from Cyclodextrin Technologies Development, Inc. (Gainesville, Fla.). The OVA (500 ug/ml in normal saline) is mixed with equal volumes of 10% (wt/vol) alum in distilled water. The mixture (pH 6.5 using 10 N NaOH) after incubation for 60 minutes at room temperature is centrifuged at 750 g for 5 minutes; the pellet resuspended to the original volume in distilled water and used within one hour. The selective 5-lipoxtgenase inhibitor, Zileuton (N-[l-benzo[b]thien-2-ylethyl]-N-hydroxyurea; J. Pharmacol Exp Ther. 1991; 256: 929-937) is dissolved in Trappsol.TM. Histatek, Inc. (Seattle, Wash.) to provide the mast cell degranulation inhibitor, f-Met-Leu-Phe-Phe ("HK-X").
Female BALB/c Once (6-8 wk of age) receive an i.p. injection of 0.2 ml (100 ug) of OVA with alum on the different protocols of Standard (J. Exp Med. 1996; 184: 1483-1494). Mice are anesthetized with 0.2 ml i.p. of ketamine (0.44 mg/ml)/xylazine (6.3 mg/ml) in normal saline before receiving an intranasal (i.n.) dose of 100 ug OVA in 0.05 ml normal saline and an i.n. dose of 50 ug OVA in 0.05 ml normal saline separately on different days. Two control groups are used: the first group receives normal saline with alum i.p. and normal saline without alum i.n. ; and the second group receives OVA with alum i.p., OVA without alum i.n., and normal saline, alone.
The trachea and left lung (the right lung may be used for bronchoalveolar lavage ("BAL") as described below) are obtained and fixed in 10% neutral formaldehyde solution at room temperature for about 15 h. After being embedded in paraffin, the tissues are cut into 5-um sections and processed with the different staining or immunolabling further. Discombe's eosinophil staining is used for counting the cell numbers with the counterstain of methylene blue. The eosinophil number per unit airway area (2,200 urn2) is determined by morphometry (J. Pathol. 1992; 166: 395-404; Am Rev Respir Dis. 1993; 147:448- 456). Fibrosis is identified with the Masson's trichrome staining. Airway mucus iss identified by the following staining method: methylene blue, hematoxylin and eosin, mucicarmine, alcian blue, and alcian blue/periodic acid-Schiff (PAS) reaction (Troyer, H., "Carbohydrates" in Principles and Techniques of Histochemistry, Little, Brown and Company, Boston, Mass., 1980: 89-121; Sheehan, D. C, et al., "Carbohydrates" in Theory and Practice of Histotechnology, Battle Press, Columbus, Ohio, 1980: 159- 179) Mucin is stained with mucicarmine solution; metanil yellow counterstain is employed. Acidic mucin and sulfated mucosubstances are stained with alcian blue, pH 2.5; nuclear fast red counterstain is used. Neutral and acidic mucosubstances are identified by alcian blue, pH 2.5, and PAS reaction. The degree of mucus plugging of the airways (0.5-0.8 mm in diameter) is also assessed by morphometry. The percent occlusion of airway diameter by mucus iss classified on a semiquantitative scale from 0 to 4+. The histologic and morphometric analyses may be performed by individuals blinded to the protocol design.
On day 28, 24 hours after the last i.n. administration of either normal saline or OVA, pulmonary mechanics to intravenous infusion of methacholine may be determined in mice in vivo by a plethysmographic method as previously described (10, 1958; 192: 364-368; J. Appl. Physiol. 1988; 64: 2318-2323; J. Exp. Med. 1996; 184: 1483-1494).
After tying off the left lung at the mainstem bronchus, the right lung may be lavaged three times with 0.4 ml of normal saline. Bronchoalveolar lavage (BAL) fluid cells from a 0.05-ml aliquot of the pooled sample are counted using a hemocytometer and the remaining fluid centrifuged at 4°C. for 10 minutes at 200 g. The supernatant may be stored at 70.degree. C. until eicosanoid analysis is performed. After resuspension of the cell pellet in normal saline containing 10% bovine serum albumin ("BSA"), BAL cell smears are made on glass slides. To stain eosinophils, dried slides are stained with
Discombe's diluting fluid (0.05% aqueous eosin and 5% acetone (vol/vol) in distilled water; J. Exp. Med. 1970; 131 : 1271-1287) for 5-8 minutes, rinsed with water for 0.5 minutes, and counterstained with 0.07% methylene blue for 2 minutes. While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims

A compound of
Figure imgf000085_0001
or a pharmaceutically acceptable salt thereof, wherein:
A is a group selected from:
Figure imgf000086_0001
Figure imgf000086_0002
85
Figure imgf000087_0001
p is from 0 to 3;
s is from 0 to 3 ;
R is: hydrogen; or Ci-6alkyl which may be unsubstituted or substituted one or more times with halo; and
each Re is independently: hydrogen; Ci-6alkyl; halo; Ci-6alkoxy; or cyano; wherein the Ci-6alkyl moieties may be unsubstituted or substituted one or more times with halo.
2. The compound of claim 1, wherein the compound is selected from:
methyl 4-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]tetrahydropyran-4-carboxylate;
methyl 4-[2,5-difluoro-4-[[(3S,6S)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]tetrahydropyran-4-carboxylate;
(3S,6R)-2-[[2-fluoro-4-[4-(oxetan-3-ylmethoxymethyl)tetrahydropyran-4-yl]phenyl]methyl]-3- methyl-6-phenyl-thiazinane 1 , 1 -dioxide;
(2S)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-(oxetan-3-yl)propanamide;
(2R)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-(oxetan-3-yl)propanamide;
(2R)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-tetrahydropyran-4-yloxy-acetamide; (2S)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-tetrahydropyran-4-yloxy-acetamide;
(2R)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-(oxetan-3-yloxy)acetamide;
(2S)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-(oxetan-3-yloxy)acetamide;
(2S)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-hydroxy-2-methyl-propanamide;
(2R)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-hydroxy-2-methyl-propanamide;
2- [[6- [2,5-difluoro-4- [[(3 S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-oxaspiro[3.3]heptan-6-yl]oxy]acetamide;
2- [[6- [2,5-difluoro-4- [[(3 S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-2-oxaspiro[3.3]heptan-6-yl]oxy]-N-methyl-acetamide;
(3S,6R)-2-[[4-(6-allyloxy-2-oxaspiro[3.3]heptan-6-yl)-2,5-difluoro-phenyl]methyl]-3- methyl-6-phenyl-thiazinane 1 , 1 -dioxide;
3- [2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]cyclobut-2-en-l-one;
(2S)-4-cyano-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]butanamide;
(2R)-4-cyano-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]butanamide;
(2R)-2-(cyclopropylmethoxy)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl- thiazinan-2-yl]methyl]phenyl]acetamide;
(2S)-2-(cyclopropylmethoxy)-2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl- thiazinan-2-yl]methyl]phenyl]acetamide;
2- [[ 1 - [2,5-difluoro-4- [[(3 S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl] methyl]phenyl] - 1 -methyl-ethyl] amino] acetamide;
2- [[ 1 - [2,5-difluoro-4- [[(3 S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3,3-difluoro-cyclobutyl]amino]acetamide; 3-[[(lR)-l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]amino]cyclohex-2-en-l-one;
3- [[(lS)-l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]amino]cyclohex-2-en-l-one;
4-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]- 1 -methyl-2-oxabicyclo[2.1.1 ]hexan-3-one;
N Γ - [ 1 - [2,5 -difluoro-4- [ [(3S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-Nl-methyl-2-nitro-ethene-l,l -diamine;
2-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethylamino]acetamide;
N-cyclopropyl-4-[3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]tetrahydropyran-4-carboxamide;
N-(cyclopropylmethyl)-4-[3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan- 2-yl]methyl]phenyl]tetrahydropyran-4-carboxamide;
4-[3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]-N- (3-methoxycyclobutyl)tetrahydropyran-4-carboxamide;
4- [3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]-N- [(2R)-2-hydroxypropyl]tetrahydropyran-4-carboxamide;
4-[3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]-N- (3-hydroxycyclobutyl)tetrahydropyran-4-carboxamide;
4-[3-fluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]-N- [l-(hydroxymethyl)cyclopropyl]tetrahydropyran-4-carboxamide;
N-( 1 -cyanocyclopropyl)-4- [3 -fluoro-4- [ [(3S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan- 2-yl]methyl]phenyl]tetrahydropyran-4-carboxamide;
4-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]- N-(3-hydroxycyclobutyl)tetrahydropyran-4-carboxamide;
4-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]- N-(3-hydroxycyclobutyl)tetrahydropyran-4-carboxamide;
(3S,6R)-2-[[2,5-difluoro-4-[(3S,4R)-3-fluoro-4-(l,2,4-triazol-4-yl)-l- piperidyl]phenyl]methyl] -3-methyl-6-phenyl-thiazinane 1 , 1 -dioxide; (3S,6R)-2-[[2,5-difluoro-4-[(3R,4S)-3-fluoro-4-(l ,2,4-triazol-4-yl)-l- piperidyl]phenyl]methyl] -3-methyl-6-phenyl-thiazinane 1 , 1 -dioxide;
N-cyclopropyl-2-[4-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]tetrahydropyran-4-yl]oxy-acetamide;
2- [[ 1 - [2,5-difluoro-4- [[(3 S ,6R)-3 -methyl- 1 , 1 -dioxo-6-phenyl-thiazinan-2- yl] methyl]phenyl] - 1 -methyl-ethyl] amino] acetamide;
(lR,5S)-l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l ,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-oxabicyclo[3.1.0]hexan-2-one;
3- (cyanomethyl)-l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl] methyl]phenyl ] cyclobutanecarboxamide ;
3-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l ,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethylamino]-3-(methylamino)prop-2-enenitrile;formic acid;
N-[3-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]oxetan-3-yl]cyclopropanecarboxamide;
(lR,5S)-l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l ,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]-3-oxabicyclo[3.1.0]hexan-2-one and
2-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]- 2-phenyl -ethanol . 3. A compound of formula II
Figure imgf000090_0001
or a pharmaceutically acceptable salt thereof,
wherein:
p is from 0 to 3;
q is from 0 to 3;
s is from 0 to 3 ; Het is heteroaryl selected from: oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; pyrazolyl;triazolyl; oxadiazolyl; thiadiazolyl; pyridinyl; pyrimidinyl; pyrazinyl; or imidazolyl;
A is: -CH(CH3)-NRa-CH2-; -CH(CH3)-NRa-C(0)-; or -CH(CH3)-NRa-C(0)-CH2-;
R is: hydrogen; or Ci-6alkyl which may be unsubstituted or substituted one or more times with halo;
each R9 is independently: Ci-6alkyl; halo; Ci-6alkoxy; or cyano; wherein the Ci-6alkyl moieties may be unsubstituted or substituted one or more times with halo;
each R10 is independently: Ci-6alkyl; hydroxy; oxo; cyano; halo; hydroxy-Ci-6alkyl; or C i_6alkoxy-C i-6alkyl ;
Ra is: hydrogen; or Ci-6alkyl and
each Re is independently:
hydrogen;
Ci_6alkyl;
halo;
Ci_6alkoxy; or
cyano;
wherein the Ci-6alkyl moieties may be unsubstituted or substituted one or more times with halo. 4. The compound of claim 3, wherein the compound is selected from:
l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]- N-(isoxazol-4-ylmethyl)ethanamine;
l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]- N-(oxazol-4-ylmethyl)ethanamine;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]isoxazole-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-5-methyl-isoxazole-3-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-2-isoxazol-4-yl-acetamide; N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-3-methyl-lH-pyrazole-4-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-3-methyl-lH-pyrazole-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]pyrazine-2-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-l-methyl-pyrazole-3-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-lH-imidazole-4-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-3-methyl-isoxazole-4-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-l-methyl-pyrazole-4-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-l-methyl-imidazole-4-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]pyrimidine-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-4-methyl-oxazole-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]oxazole-4-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]pyrimidine-4-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-3-methyl-isoxazole-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl] methyl]phenyl]ethyl] - 1 H-pyrazole-3 -carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-2-methyl-pyrazole-3-carboxamide; 3-arnino-N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-lH-l,2,4-triazole-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]thiazole-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-5-methyl-l,3,4-oxadiazole-2-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]-3-methoxy-isoxazole-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]oxazole-5-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]isoxazole-3-carboxamide;
N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]isoxazole-3-carboxamide;
2-arnino-N-[l-[2,5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]thiazole-4-carboxamide; and
N-[l-[2,
5-difluoro-4-[[(3S,6R)-3-methyl-l,l-dioxo-6-phenyl-thiazinan-2- yl]methyl]phenyl]ethyl]thiadiazole-4-carboxamide.
A composition comprising:
(a) a pharmaceutically acceptable carrier
(b) a compound of any of claims 1 to 4.
6. A method for treating a disease selected from rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, juvenile arthritis, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), psoriasis, biliary colic, renal colic, diarrhea-dominant IBS, muscular sclerosis, Sjogren's disease, lupus, and pulmonary fibrosis, the method comprising administering to a subject in need thereof an effective amount of a compound of any of claims 1 to 4.
7. The use of a compound any one of claim 1 to 4 for the treatment or prophylaxis of rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, juvenile arthritis, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), psoriasis, biliary colic, renal colic, diarrhea-dominant IBS, muscular sclerosis, Sjogren's disease, lupus, and pulmonary fibrosis.
A compound of any one of claim 1 to 4 for the treatment or prophylaxis of rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, juvenile arthritis, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), psoriasis, biliary colic, renal colic, diarrhea- dominant IBS, muscular sclerosis, Sjogren's disease, lupus, and pulmonary fibrosis.
The use of a compound of any one of claim 1 to 4 for the preparation of a medicament for the treatment or prophylaxis of rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, juvenile arthritis, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), psoriasis, biliary colic, renal colic, diarrhea-dominant IBS, muscular sclerosis, Sjogren's disease, lupus, and pulmonary fibrosis.
The invention as hereinbefore described.
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